Rheological treatment methods and related apheresis systems

ABSTRACT

Therapeutic apheresis treatments and diagnostic monitoring methods are described, specifically relating to the depletion and/or removal of a broad bandwidth of certain rheologically active elements from the blood of a patient followed by return of the blood so treated to the patient, and to methods or procedures of apheresis treatment, especially biophysiologic blood filtering treatments and computer medicated delivery methods configured to provide such apheresis treatments to patients with certain chronic, age-related, degenerative, atherogenic, thrombotic or inflammatory diseases; especially those associated with RAM accumulation-deposition causing disturbances of blood rheology or microcirculatory impairment.

RELATED CASES

This application is based on U.S. Provisional Application Ser. No.60/114,144, filed Dec. 29, 1998 and U.S. Provisional Application Ser.No. 60/158,049, filed Oct. 7, 1999, these applications being herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates generally to the treatment of various disorderscaused by or associated with relatively elevated levels of certain highmolecular weight blood plasma components, particularly thoserheologically active macromolecules that generally are larger than about500,000 Daltons (500 kDa) in weight or greater than about 200 Å indiameter. Elevated levels of such plasma constituents are found inchronic, age-related, degenerative, and/or inflammatory diseasesassociated with the accumulation of and/or deposition of biologicalsubstances that result in or are associated with disturbances of bloodrheology, extra-cellular matrix composition, and intrinsic endothelialcell function. The invention relates specifically to Rheopheresis® bloodfiltration treatments, and associated membrane differential filtrationdevices, methods, treatment apparatus and systems for such diseases, andmore particularly to the treatment of atherosclerotic and/or thromboticdiseases such as coronary, renal, peripheral and cerebrovasculardiseases as well as perfusion deficit diseases such as Age-relatedMacular Degeneration (AMD), Diabetes, Rheumatoid Arthritis andAlzheimer's Disease. Such methods include but are not limited toVasoTherapy™ and AngioTherapy™ using the RheoFilter AR 3000 andRheoFilter AR 4000 hollow fiber membranes respectively. Thus, for thepurposes of this application, as will be evident from the context, theterm “rheopheresis” applies broadly to each of these methods and filterscollectively, although they include different products, are directedtoward different disease manifestations and are studied, labeled,tested, approved, utilized and reimbursed differently.

BACKGROUND OF THE INVENTION

Circulating blood components that are suspended in or dissolved in theplasma can be loosely classified into (1) small (low molecular weightcompounds), (2) medium or “middle molecules” and (3) large (highmolecular weight compounds). The relationship between the size andweight of these compounds is determined by: (1) their density, which isdirectly related to the three-dimensional conformational structure(protein folding) of the isoform expressed and (2) their biologicallyactive form (monomer vs. multimer). Small plasma compounds are typicallyless than 75 Å in their shortest axis diameter and have low molecularweights generally less than about 120,000 Daltons (120 kDa). Middlemolecules occupy the range roughly from about 75 Å to 150 Å in theirshortest axis diameter, weighing 120 kDa to 500 kDa. Large plasmacomponents are those typically larger than about 150 Å in their shortestaxis diameter weighing generally greater than 500 kDa.

Typical low molecular weight moieties include substances such as albumin(69 kDa) and certain cytokines such as tumor necrosis factor (TNF-alpha)and certain growth factors (VEGF, TGF-beta, etc.). Middle molecules mayinclude the gamma immune globulins (˜125 kDa) and similar-sizedparticles. The high molecular weight group includes the “rheologicallyactive macromolecules” (RAM) compounds such as the alpha-2 macroglobulintetramer (˜900 kDa), lipoproteins A and B, cholesterol isoforms (VLDL,LDL, IDL, etc) and other beta lipoproteins (˜850 kDa), fibrinogen, IgM,and many others. Many of these compounds can exist in numerous relatedisoforms, such as racemers, enantiomers, oxidized and reduced forms, andso on. Frequently, the biologically active state of plasma componentparticles is conferred in multimeric conformations such as IgApentamers, TNF-alpha dimers, vitronectin 16-mers and von Willebrandtrimers. Often their biological activity will change depending upon theisoform expressed. They are often categorized into groups, classes,families, and superfamilies.

Many high molecular weight RAM compounds are associated with variousdiseases that may be treated according to the methods of the presentinvention.

1. Diseases Associated with High Molecular Weight Compounds in thePlasma

Historically, diseases have been classified as being either ‘acute’ or‘chronic’ in nature. Recently it has been determined that many chronicillnesses, especially some age-related, degenerative, and inflammatorydiseases, result from pathologies involving either: (1) a slowlyprogressive, chronic, time-dependent accumulation of biological moietiesinto tissues comprised, in some cases, of metabolic debris, or (2) inother cases of the rapid, acute, up-regulated overproduction of thesesame substances where they can exhibit acute phase reactant behavior.

Irrespective of their origin, mechanism of formation or temporalgeneration, in those disease states referenced above, these biologicalproducts have a tendency to collect within peri-endothelial, capillary,interstitial, and extracellular matrix tissues. Although they aretypically distributed across all three body compartments (intravascular,interstitial and intracellular), depending upon their equilibriumconstants and the homeostatic disruption, they will often manifest asincreased plasma or serum concentrations within the blood circulationitself. Often, these biological compounds are further modified byacetylation, glycation, oxidative or other processes to form less stableisoforms that condense into complex aggregates (atherosclerotic plaques,drusen, neurofibrillary tangles, lipofuscin, amyloid, etc.). Althoughthese aggregates are comprised primarily of proteinaceous moieties, theyalso contain lipids, lipoproteins, fatty acids, carbohydrates, metalsand other non-protein compounds. Thus, the terms “proteinaccumulation-deposition diseases” or “dysproteinemias” as has beenhistorically applied to these conditions, is technically a misnomer.Therefore, for the purposes of this application, the term “RAMaccumulation-deposition diseases” will be substituted for clarificationwhere appropriate.

Saturated catabolic mechanisms predispose RAM to progressiveconcentration increases within the blood that primarily and secondarilyinduce numerous functional disturbances of the endothelium, bloodrheology, extra-cellular matrix, microcirculation and/or microperfusion.Elevated serum levels of RAMs have been documented to:

(1) cause increases in whole blood and plasma viscosities thus reducingblood flow;

(2) promote cell-cell adhesion causing thrombosis, cell clumping anddiapedesis;

(3) disrupt numerous intrinsic endothelial cell functions, and (4) causenumerous other pathologies which can promote various disturbances in themicrocirculation. Such actions are measurable as decreases in capillaryperfusion, endothelial cell rupture, atherogenesis, thrombosis,angiogenesis, and other pathological states leading to ultimateend-organ dysfunction or outright failure. Occasionally, primaryrheologic pathologies can be so significant that the disturbances can beobserved even within the systemic circulation forming procoagulantstates and in the extreme—hyperviscosity syndromes, diffuseintravascular coagulation, etc.

Some examples of medical conditions that may be classified as RAMaccumulation-deposition diseases are:

Atherosclerotic disease which develops as a result of progressiveendothelial cell dysfunction in the presence of progressive depositionof lipid-laden plaques that form preferentially within the intimal wallsof coronary, renal, carotid, aortic and certain other arteriesthroughout the body, often in the presence of hyperlipidemia.

Rheumatoid arthritis which results from the destructive inflammatoryreactions occurring in a synovial pannus associated with elevated serumlevels of Rheumatoid Factor, various inflammatory proteins, immunologicglobulins, integrins, and other compounds, including the chemotacticattraction of activated inflammatory cells, that contribute to thedysfunctional synovial lining of the various joints involved;

Diabetes mellitus which is classically described as an autoimmunedisease demonstrating profound pathological effects on themicrocirculation and peripheral nervous system, with classicallyobserved disruptions of blood rheology associated with aldosedeposition, and other disruptions including: advanced glycation,carbohydrate dysmetabolism, insulin resistance and otherpathophysiologic disturbances measured in both the serum and tissues;

Alzheimer's disease which is associated with the formation of“neurofibrillary tangles” or accumulations of complex deposits comprisedprimarily of Tau proteins and beta-amyloid proteins in specific braintissues, and is also associated with decreased local blood flow to thosesame brain tissues;

Age-related macular degeneration (“AMD”), which is often characterizedby the deposition of vitronectin, lipofuscin aggregates called drusenand basilar laminar deposits which form within specific retinal tissues(the retinal pigment epithelium/Bruch's Membrane complex) and isassociated with a disruption of the choriocapillary microcirculation, aswell as observed increases in the serum levels of certain circulatingRAMs (cholesterol, fibrinogen, etc.).

Procoagulant State which is often characterized by (relatively increasedserum concentrations of certain thrombogenic macromolecules causing) atendency to relatively more readily activate the coagulation cascade ina patient.

2. Rheologically Active Macromolecules (RAMs)

RAMs are typically large, high molecular weight biological moieties,comprised primarily of proteins and lipids, and secondarily of fattyacids, carbohydrates and other compounds that are found in the generalblood circulation, in the membranes of blood cells, expressed on cellsurfaces (especially endothelial cells), deposited in the extra-cellularmatrix and within the interior of cells of certain tissues. RAMs areassociated with unique pathological roles and physiological effects asdescribed above.

In addition to their unique biochemical roles, RAMs exert numeroussecondary and tertiary effects on the blood and blood rheologyprocesses, including acting as buffers, osmotic agents, oncotic agents,signaling molecules, and so on. More specifically, many RAMs exertcomplex, simultaneous and integrated rheological effects on the bloodcells themselves including: (1) red cell aggregation andviscoelasticity; (2) leukocyte adhesion, morphogenesis and diapedesis;and (3) platelet rouleaux formation. These actions are primarilymediated by the regulatory effects of RAM on gene activation and surfacereceptor expression on these blood cells, and ultimately reflect on bothwhole blood and plasma viscosities, with primary control over bloodflow, shear stress and perfusion within the microcirculation. Theseeffects are transmitted to the macrocirculation via the vaso-vasorumthat nourishes the entire vascular system. Recent research also pointsto certain RAMs acting as triggers for various gene expressions, andmRNA transcription activity as well, especially in their role inapoptosis (programmed cell death).

Examples of circulating soluble or suspended RAMs commonly measured inthe serum of patients are: alpha-2 macroglobulin, fibrinogen,triglycerides, beta-lipoproteins like LDL cholesterols (especially theoxidized forms), fibronectin, vitronectin, IgM, and otherimmunoglobulins, von Willebrand factor, lipoprotein A, to name just afew. Of course, there are some RAMs less than 500 kDa, however most RAMsare greater than 500 kDa. One object of the present invention is thesafe, rapid, efficient and simultaneous depletion of at least two ormore of these RAMS from the systemic circulation and by their extractionfrom the tissues. The close association of these markers and thediseases that they herald and/or play a causative role, allow thesemoieties to be commonly referred to as “risk factors” or “serologicalmarkers” for the development of the diseases with which their serumelevations are correlated (heart disease, stroke, renal failure,blindness, etc., in association with cholesterol, fibrinogen, etc.)

3. Apheresis to Modulate Plasma Levels of RAMs

It is now widely accepted that RAM either directly or indirectlyparticipate in the control of virtually every aspect of vascularcellular metabolic activity. They govern the intricate balance of actionand reaction that controls the many complex biochemical reactionsnecessary to maintain health (homeostasis). The precise homeostaticcontrol mechanisms vary from one endothelial population to another, butgenerally speaking, most RAM can be classified into having one of twoactions, promoters—which activate or “up-regulate” a particularbiological action, pathway or process—and inhibitors—which suppress or“down-regulate” a particular biological action, pathway or process.Interestingly, depending upon their local concentration levels, many RAMcan exhibit both actions—acting like biological switches.

In health, the body responds to the overproduction or under-catabolismof a particular substance by increasing its endogenous production ofmediators, which can include a cascade of promoters, inhibitors, orboth, as the case may be designed to reduce its concentration back downto normal limits. Conversely, any underproduction or over-catabolism iscounteracted with a concomitant release of mediators that likewise caninclude a cascade of promoters, inhibitors, or both, as the case may bedesigned to increase its concentration back up to normal limits. Anyprolonged disruption of this delicate balance of promoters andinhibitors can lead to a pathologic deterioration of the clinical stateinto conditions that ultimately manifest themselves as disease. Manydiseases manifest themselves as deficiencies of essentialmacromolecules, RAM accumulation-deposition diseases are easilydifferentiated by characteristically being associated with excessiveconcentrations of macromolecules. It is now thought that theseimbalances are initially manifested at the molecular level wherechemical reactions located in sub-cellular organelles, usually underprotein (enzymatic/hormonal) control, determine the ultimate overtclinical status. However, within the bloodstream itself, numeroushomeostatic mechanisms have evolved that are regulated not only by thechemical reactions of certain moieties, such as RAMs, but also aredirectly affected by the absolute plasma concentrations of thesecomponents in circulation, such as the rheologic effects. Often, theseeffects can be greatly accelerated and exaggerated as can be seen inorgan failure like the nephrotic syndrome where intravascular plasmalosses induce artificially elevated plasma concentrations of RAMs.

A. Plasmapheresis

Increasingly sophisticated apheresis technologies have contributed toadvanced methods of providing the two basic forms of apheresistreatment, namely plasmapheresis and cytapheresis. Plasmapheresisinvolves the extracorporeal manipulation, depletion and/or removal ofcertain soluble or suspended elements in the plasma portion of theblood, and then returning the blood so treated to the patient to inducea desired clinical effect. Historically, these methods have beenprimarily concentrated on modulation of immune pathologies.Plasmapheresis is variously performed in vivo using therapeutic plasmaexchange (TPE), immunoadsorption (IA), precipitation (HELP), membranedifferential filtration (MDF), and other means.

By way of example, one type of plasma filtration column is described inU.S. Pat. No. 4,619,639 (which issued to Asahi Medical Company, Ltd. in1986).

B. Cytapheresis

Cytapheresis can be distinguished from plasmapheresis in that itinvolves the extracorporeal manipulation or depletion and/or removal ofvarious circulating or marrow-bound cellular elements in the blood (redcells, white cells, stem cells or platelets) or specific subpopulationsof these cells in order to induce a desired clinical effect.Historically, these effects have been primarily concentrated onmodulation of hypercellular pathologies like leukemias, myelomas etc. Itis variously performed with centrifuge, membrane differentialfiltration, and other means.

C. Apheresis Equipment

Several new apheresis methods including membrane differential filtration(MDF) systems, utilizing for instance the PlasmaFlo® OP-05(W)L and theRheoFilter® AR2000 blood filters, both manufactured by Asahi MedicalCompany, Ltd. of Japan, and other such devices, have recently beenintroduced. These filter combinations have demonstrated the ability tosafely and effectively reduce significant concentrations of a broadbandwidth of numerous circulating plasma macromolecules, including;alpha-2 macroglobulin, triglycerides, the cholesterol family ofbeta-lipoproteins, various immunoglobulins, fibrinogen, advancedglycation modified end products (i.e., AGE-modified lipoproteins), andthe like. These MDF apheresis devices employ sophisticated membranesthat utilize the presence of porous hollow fibers that sieve out variousblood constituents depending upon the pore size in the fiber's sidewall.Accurate control of the average pore size of the fibers within thefilters enables one to selectively sieve out only the particular size orweight macromolecules desired above a certain “cut-off” threshold. TheRheoFilter AR 2000 for example, has average pore sizes of 250 Å indiameter (about the size of the typical LDL molecule). In theory,depending upon the pore size cut-offs, several filters of differing poresizes can be placed in series to remove specific components from theblood of virtually any size range.

Other benefits of MDF systems include the application of plasmaseparation as that performed by the Plasmaflo OP-05 (W)L that operatesusing low operating trans-membrane pressures such that virtually nohemolysis of the blood occurs during treatment. This represents asignificant advance over the centrifuge technologies currently in wideuse in the United States and elsewhere. As would be expected, whereverhollow fiber membranes have been introduced, the use of centrifugesystems has been significantly reduced.

4. Various Diseases Treated by Apheresis

A variety of apheresis treatments have been described over the pastthirty years for use with patients having acute illnesses. However,patients with chronic, age-related, degenerative, or inflammatorydiseases, especially those manifesting disturbances of blood rheology,differ significantly from the historical acutely ill populations thatheretofore have obtained plasmapheresis treatment. For example,chronically ill patients are typically significantly older than patientswith acute conditions, often have significant co-morbidities (heartdisease, etc.), consume numerous medications, and in general aretypically less robust (resilient) than the younger acute patient group.Among other things, since many of the chronic, age-related,degenerative, inflammatory diseases are initiated, moderated, orotherwise associated with a disruption of capillary blood flow and/or adysregulation of microperfusion to a diseased or failing organ and sucha condition is typically systemic, other organ systems may be diminishedin their intrinsic functional capacities as well. Accordingly, the useof apheresis to treat such chronically ill patients has been relativelylimited. One recent exception is hyperlipidernia.

A. Hvpercholesterolemia

Several apheresis systems have recently has been introduced for thetreatment for patients with clinically evident, refractory, drugresistant, Type II Familial Hypercholesterolemia—a rare chronic, slowlyprogressive, ultimately fatal illness. (Matsuda et al., (1995)Artificial Organs 19, 129-134). One observed consequence of the LDLreduction via apheresis both with and without adjunctive lipid-loweringpharmaceutical therapy has been the reduction of the incidence ofrestenosis after revascularization as well as a reduction of coronaryevents.

B. Autoimmune Disorders

Apheresis means have been employed to treat various autoimmunedisorders. Depending upon the disease itself, its clinicalmanifestations, and the underlying mechanism of action, apheresissystems have been effective either as primary or adjunctive therapies.Some examples are listed below:

1) Lupus Erythematosis

Standard treatment of Lupus Erythematosis consists of corticosteroidsand immunosuppressive drugs. Plasmapheresis has been shown to impartadditional benefit to patients suffering from Lupus Erythematosis whenused alone to treat acute symptoms or prior to immunosuppressive therapy(Euler et al., (1996) Transfus. Sci. 17, 245-265). The apheresis methodsare employed to remove circulating antibodies, immune complexes andantigens that contribute to the etiology and/or progression of thedisease.

2) Rheumatoid Arthritis

Apheresis has also been used to treat rheumatoid arthritis, a chronicand debilitating autoimmune disease which leads to inflammation anddeformity of the joints (U.S. Pat. No. 5,782,792). The standardtreatment involves weekly outpatient apheresis sessions utilizing acolumn containing Protein A immobilized on an inert silica matrix for 10to 12 treatments. The Protein A binds to and removes antibodies, immunecomplexes and antigens that contribute to the symptoms of rheumatoidarthritis. A similar method has also been described for treatment ofthrombotic thrombocytopenia purpura (U.S. Pat. No. 5,733,254).

C. Cryoglobulinemia

Patients diagnosed with cryoglobulinemia have been treated using variousapheresis methods with successful results (Russo et al., (1996)Transfus. Sci. 17, 499-503; Siami et al., (1995) ASAIO J. 41,m315-m318). The final results of these studies indicated that treatmentwith apheresis resulted in a reduction in plasma viscosity andsubsequent improvement in rheology and in the function of affectedorgans.

D. Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a chronic, progressive,degenerative eye disease of unknown etiology. AMD is characterized byprogressive loss of central vision, and is the most common cause oflegal blindness in patients over age 65 in the industrialized world.Over fifteen million Americans are currently estimated to be diagnosedwith signs and symptoms of AMD, most commonly in persons aged 65 andolder, with over one and a half million rendered legally blind andnearly two million new cases being diagnosed annually. AMD is dividedinto “Dry” and “Wet” forms depending upon the morphologicalcharacteristics associated with the observed eye pathology.

Recently, Allikmets and others presented landmark research thatimplicates a defective gene in the pathogenesis of AMD (Allikmets etal., (1997) Science 277, 1805-1807). The gene, which is located at thelp21 locus, codes for the manufacture of the ATP Binding Cassettetransporter retina-specific (ABCR) protein. This superfamily of proteinsis believed to be responsible for energy-dependent transport of varioussubstances across retinal membranes, thus promoting the clearance of theretina's waste by-products of vision. In both rod and cone outersegments, hundreds of pigment disks are shed into the retinal pigmentepithelial layer (RPE) of the retina daily. There the RPE cellsphagocytize the pigment disk material, preparing it for transport acrossBruch's membrane to be removed by the adjacent choriocapillary bloodsupply.

The reported genetic defect in AMD renders this waste removal pipelineless effective, allowing accumulations of debris to collect in theposterior retina at the layer of the RPE/Bruch's complex. Whenclinically evident, this debris is believed to collect in depositstermed drusen or basilar laminar deposits, depending upon the locationof the deposit. It is believed that these deposits are directly toxic tosurrounding retinal tissues, and that they may play a role in theprogression of AMD. If so, depletion and/or removal of these deposits ishypothesized to have a beneficial effect on a patient's vision. Currentresearch attempts to improve patients' vision by laser applications tothese drusen deposits have been disappointing.

Other recent research supports the notion that AMD is concurrentlyassociated with a dysfunction of the microcirculation in the posteriorretina (Freidman et al., (1997) Am. J. Opthalmol. 124, 677-682; andGrunwald et al., (1986) Opthalmology 93, 590-595).

This body of research has repeatedly documented decreases in retinalblood flow, impaired choriocapillary perfusion, increased vascularresistance, and pulsatility, along with decreased blood volume andvarious morpho-pathologic changes in the retinal capillary vesselsthemselves. Although the precise etiology and mechanism of action forthe occurrence of these changes are not yet understood, it is believedthat AMD is promoted through a complex interaction of multipleetiologies. Therefore, until now, other than laser photocoagulation,there has been no therapy widely recognized to be effective andtherefore commonly recommended for the treatment of this disease, andmost certainly in its early “dry” stages.

Brunner, Berrouschot and others have documented that subsequent to MDFapheresis, reduction of rheologic factors induces numerous clinicallyevident rheological changes, including reduction of both whole blood andplasma viscosities, reduction of red blood cell aggregation, promotionof capillary blood flow, and enhancement of intrinsic endothelial cellfunction (Brunner et al., (1995) Intl. J. Artif. Organs 18, 794-798;Brunner et al., (1991) JAMA 18, 63-65; Brunner et al., (1996) Transfus.Sci. 17, 493-498; Widder et al., Invest. Opthalmol. Vis. Sci. 38,s1-1176; Berrouschot et al., (1998) Acta. Neurol. Scand. 97, 126-130).These prior studies, however, failed to optimize timing intervalsassociated with apheresis treatments and therefore were unable todemonstrate maximal improvement in clinical outcomes. Specifically, theAMD study utilized a monthly interval between individual apheresistreatment cycles of two session which was insufficient to maintainreduced levels of RAMs. The ischemic stroke study utilized a protocol inwhich apheresis treatment was not given until six or more hoursfollowing stroke. The apheresis treatment protocol was also consideredto be unsatisfactory because of the extended period of time prior totreatment (six hours).

E. Cancer

Other researchers have discovered and used a selective form of apheresisdesignated UltraPheresis™ as an innovative approach for the treatment ofcancer (U.S. Pat. No. 4,708,713 issued to Rigdon Lentz). UltraPheresis™removes a low molecular weight fraction of the blood containingimmunosuppressive components, known as tumor necrosis factor (TNF-alpha)soluble receptors, from the blood of the cancer patient. When TNF-alphareceptors are removed, a patient's natural killer cell activityincreases and is better able to recognize and attack the malignanttissue. UltraPheresis™ therapy thus is intended to stimulate the naturalimmune response that is suppressed by malignant tissue expression oftumor recognition suppressive agents. UltraPheresis™ can bedistinguished from Rheopheresis® blood filtration because the formerseeks to target the depletion of a specific small molecular weightfraction (less than 100 kDa) from the patient whereas the latterdepletes the entire bandwidth of the high molecular weight fraction(greater than 500 kDa).

F. Renal Diseases

Apheresis has been shown to be an effective method for the treatment ofmany types of renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome and many others as well. (Haradaet al., (1998) Ther. Apher. 2:193-198). However, the present inventionis the first to contemplate the simultaneous use with dialysis for thesecondary prevention and prophylaxis of the vascular complicationsassociated with hemodialysis treatment.

G. Acute Coronary Syndromes, Brain Stroke and Other Vascular Diseases

The utility of various apheresis methods in the treatment of variousvascular diseases is currently under investigation. While the precisemechanisms of atheroma development have not been entirely defined, themost recent consensus states that atherosclerotic lesions develop as theresult of biochemical cascades initiated in the presence of increasingplasma concentrations of certain lipids, proteins and othermacromolecules that promote accumulations of proteaceous lipid-ladenplaques within certain arterial walls. If these plaques rupture and leadto thrombosis and occlusion in the heart, this is called a heart attack,in the brain, this is called a stroke, in the limb this blood clot maylead to gangrene and amputation. Aneurysmal ruptures may follow asimilar progression.

Apheresis methods, and membrane differential filters, like theRheoFilter™ MDF system in particular, have demonstrated their ability toremove circulating plasma macromolecules that have been implicated incapillary (endothelial) dysfunction, atherogenesis and thrombosis. Themechanisms are complex but likely include alterations of rheologicfactors promoting synergies of: decreasing plasma viscosity, decreasingwhole blood viscosity, decreasing erythrocyte aggregation, increasingshear stress and enhancing intrinsic endothelial cell function. Membranedifferential filtration achieves these objectives, primarily throughreductions of circulating macromolecules, especially the RAMs withinminutes to hours.

For apheresis applications involving the treatment of vascular diseases,the ability to remove RAMs is of utmost importance. Recent research hasdemonstrated that fibrinogen, LDL, C-reactive protein, lipoprotein A andother circulating macromolecules have been associated as independentrisk factors for the development of vascular disease. As describedabove, these moieties appear to have the ability to act both as acutephase reactants as well as chronic procoagulant modifiers. In addition,these molecules have been documented to precipitate and/or exacerbatethe majority of endothelial injury response, vascular smooth muscle cellproliferation and modify extracellular matrix processes and integratedmechanisms associated with acute vascular events as well as participatein “oxidative stress” and “carbonyl stress” that up-regulate vascularinjury on the molecular level. The MDF system of the present inventionis able to suppress this overreaction by depleting the wide range ofmolecular substrate reactants consumed by the biochemical maelstrom thatoccurs acutely in such disease states and to maintain such therapeuticreductions for an extended period of time.

In the context of secondary prevention and/or acute vascular eventmanagement, truly effective interventional technologies must be able torapidly and substantially eliminate the broad spectrum of molecularpathogenic factors that have been implicated in the injury responsecascades described above. Whether such interventions are pharmacological(‘statins’) or physiologic (apheresis), they must at once preserve thosecomponents necessary for cellular repair and healing (i.e. cytokines,signaling integrins and other, typically low molecular weight proteins),while at the same time they must substantially deplete the compoundsresponsible for injury (“vascular injury risk factors”). This mandaterepresents the fundamental challenge of vascular disease management atpresent, especially given the time-to-effective-treatment requirements.

The present invention, preferably utilizing one of the RheoFilter™ MDFsystems, rapidly and efficiently depletes those circulatingmacromolecules larger than 250 Å or about 500 kDa in weight and heavier.These include; most isoforms of LDL-C, LDL-ox, fibrinogen, IgM, alpha-2macroglobulin, lipoprotein A, apolipoprotein B, von Willebrand factor,vitronectin and many others identified as potential risk factors invascular diseases. Recent studies have demonstrated that depletion ofany one of these plasma components may improve endothelial cellfunction, increase blood flow, improve clinical outcomes or promotesignificant decreases in the morbidity and mortality associated with themanagement of acute coronary and other vascular events and theirsequelae.

Other forms of apheresis for vascular intervention: In the quest forimproved outcomes beyond drug therapy alone, four LDL apheresistechnologies (dextran sulfate adsorption (Kaneka, Liposorber, Japan),antibody immunoadsorption (Baxter, Therasorb, Germany), Lp(a)immunoadsorption (Lipopak, Pocard, Russia) and heparin precipitation(HELP® System, Braun, Germany)) have recently been introduced for thetreatment of familial hyperlipidemias (elevated LDL cholesterol). Asexpected, each of these technologies demonstrates a modest incrementalability to reverse arterial plaque formation, improve blood flow andincrease exercise tolerance in some patients. However, the high costsand technical complexities associated with these methods have precludedthem thus far as widely accepted options in those markets currentlyaddressed by pharmaceutical and dietary interventions.

However, the principle reason for the lack of general acceptance is thatthe technologies are considerably too specific (removing LDL almostexclusively) to be of substantial benefit in moderating the majority ofthe mechanisms associated with acute vascular injuryresponse/reperfusion damage. The HELP® system is only slightly betterthan the others in that it additionally depletes fibrinogen and somelipoprotein A (Lp(a)). The Lipopak system is far better at removingLp(a) than any of the others, but each fails to deplete alpha-2macroglobulin, IgM, IgA multimers, fibronectin, von Willebrand Factor,C-reactive protein, and many other of the macromolecules documented tobe integral in the vascular damage cascades. This is in stark contrastto the actions of the RheoFilter® MDF systems.

5. Apheresis Treatment Facilities

A. In-Patient Medical Center Setting

Generally, the setting for therapeutic apheresis methods has beenreserved for the hospital environment treating gravely ill patients withacute life-threatening diseases or recurrent exacerbations of suchdiseases. This has primarily been due to the severity of the patientsbeing treated and subsequently the reimbursement available fortreatment. However, the current overhead expense of the hospitalenvironment adds significant costs to these procedures that need notnecessarily be applied to apheresis treatments for relatively clinicallystable yet chronically ill patients.

Historically, physicians are not trained in providing apheresistreatments outside of the hospital environment and remain unaware thatapheresis methods can be applied to treat chronic, age-related,degenerative, inflammatory diseases; with AMD serving as theprototypical example in any setting outside of the hospital. Similarly,most patients with such diseases are not aware that they have acondition potentially treatable with the apheresis methods describedherein or that such a potentially beneficial apheresis treatment optionexists in such out-patient settings.

B. Out-Patient “Office” Setting

1. Rigdon Lentz UltraPheresis™ Center

Outpatient plasmapheresis therapy has been employed for removing lowmolecular weight proteins for the treatment of certain forms of solidtumors (Lentz, (1999) Ther. Apher. 3, 40-49). This outpatient clinicpractices a selective form of plasmapheresis known as UltraPheresis™.This form of apheresis is more complicated and more expensive thanRheopheresis® blood filtration as described herein. Specifically, itremoves TNF-alpha receptors, a particular low molecular weight fraction(55-75 kDa) from a cancer patient's plasma as opposed to a highmolecular weight fraction (i.e., greater than 500 kDa).

2. LDL Apheresis Treatment

One possible exception to the exclusive use of hospital or in-patienttreatment settings involves the recent introduction of the use of LDLapheresis as a treatment for patients with clinically evident,refractory, drug resistant, Type II Familial Hypercholesterolemia—achronic, slowly progressive, ultimately fatal illness. Currently, forreimbursement purposes, LDL patients obtain their treatment in hospitalsettings located away from their medical provider. These settings remainunmodified for the specific needs of these patients. In Europe,out-patient LDL apheresis clinics are used specifically for lipidlowering in select hyperlipidemic patients, however, these facilitiesare not designed to moderate rheologic diseases, nor are they diseasespecific clinics. Neither are the treatments provided systematized to bedeliverable within an average physician's office where the “point ofsale” use can be made to conveniently provide the most patients with thebroadest available apheresis treatment options, at the lowest possiblecosts.

SUMMARY OF THE INVENTION

The present invention generally relates to therapeutic methods thatinvolve the depletion of at least two species of rheologically activemacromolecules from a patient's plasma. Preferably, such macromoleculesare depleted for a period of time and to a level that is effective toproduce an improvement in a measurable endpoint or clinical improvementin a disease associated with relatively elevated levels of rheologicallyactive macromolecules. The invention also relates to methods involvingeither the direct or indirect depletion of other plasma constituents ofthe high molecular weight fraction of plasma, and/or those constituentsresponsible for or supportive of those atherogenic, thrombotic and/orinflammatory cascades as described herein.

More specifically, the invention relates to methods in which thedepleted rheologically active macromolecules (or high molecular weightfraction of plasma constituents) include cholesterol isoforms (VLDL, LDLand IDL), triglycerides, fibrinogen, alpha-2 macroglobulin tetramers,IgM, Lipoprotein A, fibronectin, vitronectin, and IgA. Preferably thedepleted plasma constituents (or high molecular weight fraction) have amolecular weight greater than about 500,000 Daltons, or, suchconstituents (or macromolecules in such fraction) have an average sizefor a biologically active isoform that is greater than about 200 Åacross the shortest diameter.

In a preferred embodiment, the depleted components are depleted to alevel of at least about 50% of their levels in the patient compared tothat prior to treatment. In an alternative preferred embodiment, thevolume of plasma processed in a single treatment session ranges betweenabout 80% and 120% of the patient's total plasma volume. It iscontemplated that such depletion may be accomplished by Rheopheresis®blood filtration, preferably using one of the series of RheoFilter®hollow fiber membranes. Generally, the time interval between successiveRheopheresis® blood filtration treatments ranges from about one day toabout ten days and the total plasma volume processed in any one weekperiod is at least about 200% of a patient's total plasma volume, andthat the successive treatment interval prior to the next dual sessionpreferably is about 16 days±about 3 days.

It is contemplated that such therapeutic methods will be effective toproduce in the patient one or more responses, such as: (1) increasedmicroperfusion or capillary function; (2) improved immune response; or(3) extraction of tissue-bound RAM and to deplete the extracted RAM fromthe patient's plasma. Such methods generally will be effective toproduce in the patient a clinically observable improvement in a disordercharacterized by elevated plasma levels of rheologically activemacromolecules. Such disorders include: (1) age-related maculardegeneration; (2) atherosclerosis; (3) rheumatoid arthritis; (4)autoimmune diseases; (5) Diabetes; (6) Alzheimer's disease; (7)Procoagulant states, and (8) neurodegenerative diseases.

In another embodiment of the invention, Rheopheresis® blood filtrationfilters are provided in a form in which they are packaged together witha label or package insert (or the like) indicating its use for treatmentof an age-related, degenerative or inflammatory disorder characterizedby elevated plasma levels of rheologically active macromolecules, or anyof the foregoing disorders.

The present invention also encompasses diagnostic methods that involvethe measurement of the absolute or relative amounts of at least tworheologically active macromolecules depleted from a patient's plasma byRheopheresis® blood filtration. In particular, such methods involvemaking an assessment of plasma levels or rate of decrease of such levelspost treatment, then making an assessment of the concomitant increase ofthe plasma levels of the depleted rheologically active macromolecules asthey re-equilibrate toward pre-treatment levels. Patients are typicallyconsidered to have elevated levels if they are in the upper tertile oreven more preferably in the upper quartile of ranges measured for humanpatients. In these settings, patients with elevations of certain ofthese macromolecules are generally considered to be “at risk” orexhibiting a “procoagulant state”.

In a related aspect, the invention relates to methods of providingRheopheresis® blood filtration treatment. The steps of such methodspreferably include: (a) evaluating a candidate patient to identifywhether the patient has a RAM associated disease and to determine thatstate and extent of that disease; (b) determining whether the patientexhibits elevated plasma levels of at least two RAMs; (c) declining totreat patients with Rheopheresis® blood filtration who are not likely torespond to treatment or who might be harmed by the treatment; (d)selecting a particular Rheopheresis® blood filtration treatment protocolappropriate for chronic versus acute medical situations; and (e)providing Rheopheresis® blood filtration treatment. Optionally, the stepof selecting a particular Rheopheresis® blood filtration treatmentprotocol includes an evaluation of a data base containing data on otherpatients treated by Rheopheresis® blood filtration. Preferably, anadditional step is the providing of disease-specific medical follow-upevaluations. The step of submitting data on the patient to a data basecontaining data on other patients treated by Rheopheresis® bloodfiltration also is contemplated.

In another aspect, the invention relates to an integrated apheresistreatment process including the steps of: (a) providing at least onededicated out-patient, non-hospital, apheresis treatment facility; (b)locating and selecting ambulatory, community-dwelling patientspotentially capable of benefiting from apheresis treatments within acommunity that can be served by said apheresis facility; (c) identifyingand selecting from among said patients, by means which includemeasurement of serum levels of circulating rheologically activemacromolecules in said patients, a subset of patients capable ofbenefiting from apheresis treatments; (d) performing apheresistreatments in sessions on the selected patients in said dedicatedout-patient apheresis treatment facility; and (e) determining clinicalendpoints to said apheresis treatments based upon reductions in serumlevels of said rheologically active macromolecules and correlations ofclinical symptomatology through disease-specific testing and serialendpoint and clinical assessments.

In yet a further embodiment, the present invention relates to anapheresis treatment method, that includes the steps of: (a) identifyingchronically ill patients having age-related, degenerative orinflammatory diseases, the chronically ill patients being consideredcandidates for an apheresis procedure; (b) storing patient profile datafor the patient; (c) analyzing qualifying data for the chronically illpatient to determine applicability of an apheresis treatment; and (d)performing apheresis treatments in sessions on the chronically illpatient. Optionally, the storing step includes the storing at least oneof medical history data, physical characteristic data, medical conditiondata, diagnosis data, historical procedure data, and clinical effectdata. Also, optionally, the step of analyzing specifically includes oneor more of these data elements: medical history, disease specifichistory, physical examination and interview data. Such analysis stepsmay also include comparing patient profile data with a composite patientprofile that is generated using data from similar patients who havecompleted an analysis steps may also include comparing patient profiledata with a composite patient profile that is generated using data fromsimilar patients who have completed an apheresis treatment process, orthe determining of at least one or more of the probability of apheresistreatment success, a potential degree of anticipated clinical outcomesbased upon statistical normograms from an analysis of historicalcomposite patient profiles, and a most appropriate initial apheresistreatment protocol.

Another embodiment of the invention provides an apheresis treatmentqualification method, including the steps of: (a) identifying achronically ill patient having an age-related, degenerative,atherogenic, thrombotic or inflammatory disease, said chronically illpatient being considered a candidate for an apheresis procedure; (b)storing patient profile data for said identified chronically 111patient; (c) receiving, from a centralized database system, a compositepatient profile derived from other patients similarly situated to saididentified chronically ill patient; (d) comparing said patient profiledata with said received composite patient profile; and (e) determiningbased upon the comparison in step (d), whether said identifiedchronically ill patient would likely benefit from apheresis treatments.Optionally the storing step includes the storing of one or more of thepatient's medical history data, physical characteristic data, medicalcondition data, diagnosis data, historical procedure data, and clinicaleffect data.

The present invention also provides a method of screening patients for aRheopheresis® blood filtration treatment. Such method includes: (a)identifying whether the patient has a RAM associated disease anddetermining that state and extent of that disease; (b) determiningwhether the patient exhibits elevated plasma levels of at least twoRAMs; (c) selecting patients who are likely to respond to Rheopheresis®blood filtration treatment or who will not be harmed by the treatment;and, optionally, (d) selecting a particular Rheopheresis® bloodfiltration treatment appropriate for treating a specific RAM associateddisease. The method may include the screening of a data base containingpatient data from individuals treated by Rheopheresis® blood filtrationto determine the most appropriate treatment protocol. In connection withthat method, may be an additional step of submitting data in a patientprofile to a data base containing patient data from other Rheopheresis®blood filtration treatment patients.

Yet another related aspect of the present invention is a treatmentprotocol generator for use in a system that endeavors to generatedisease specific treatment protocols based on a patient profile.Preferably this treatment protocol generator comprises: (a) a treatmentprotocol derivation means for analyzing disease specific historicalcomposite patient profiles to derive treatment protocols having enhancedtherapeutic effect(s); (b) an identifying means for identifyingparticular data of a patient profile which will serve to optimize thedisease specific apheresis treatment; and (c) a treatment protocolgenerating means for generating treatment protocol that, when executed,will enable optimization of the therapeutic effect of apheresistreatment. Such treatment protocol generators also may include: (a) acomparing means for comparing said data of said patient profile againsta prescribed set of data to identify any of the treatment protocolssubstantially conforming to desired therapeutic result; and (b)classifying means for classifying the identified suitable treatmentprotocols in order of suitability based on the patient profile.

The identifying means of such a treatment protocol generator may includemeans for identifying, in accordance with said composite historicalpatient profiles, data from the database that will result a treatmentprotocol predicted to have a superior therapeutic effect. Preferably thedata includes at least one of medical history data, physicalcharacteristic data, medical condition data, diagnosis data, historicalprocedure data, clinical effect data, disease specific history data,physical examination data, and interview data. Also, preferably, thetreatment protocol generator further includes an optimal set selectingmeans for selecting an optimal set of treatment parameters based on atleast one of the following factors: (i) their respective predictedabilities to exhibit therapeutic results more closely matching theprescribed set of therapeutic results as indicated by said compositehistorical patient profiles; (ii) their respective predicted abilitiesto validate said composite historical patient profiles; (iii) theirrespective predicted abilities to discriminate between said compositehistorical patient profiles; (iv) their respective predicted abilitiesto induce superior therapeutic response; and (v) similarity betweentheir disease specific characteristics and those in composite historicalpatient profile database whose therapeutic response most closely conformto the desired therapeutic response. The protocol generator also mayinclude a means for selecting the optimal set by individually rankingthe treatment parameters based on at least one of factors (i)-(v) orcombinations thereof.

The present invention also provides an apheresis treatment datacollection and treatment system, comprising: (a) a plurality ofinterconnected computer systems located at a respective plurality ofapheresis treatment sites, said plurality of interconnected computersystems being configured to receive input reflective of apheresistreatment parameters and clinical effects produced by apheresistreatments, wherein at least one of said plurality of interconnectedcomputer systems is located at a dedicated out-patient apheresistreatment facility; and (b) a centralized database system including astorage facility that stores apheresis treatment parameter data andclinical effects data that are received from said plurality ofinterconnected computer systems, said centralized database systemfurther including a means for creating a composite patient profile basedupon apheresis treatment data that is collected for patients treated atsaid plurality of apheresis treatment sites. Optionally, the pluralityof interconnected computer systems and the centralized database systemare interconnected to form a computer network and may also be connectedto the Internet.

A related aspect of the invention provides methods for storing andprocessing input reflective of apheresis treatment parameters andclinical effects produced by apheresis treatments in a apheresistreatment data collection and treatment system, said method comprisingthe steps of: (a) configuring a plurality of interconnected computersystems located at a respective plurality of apheresis treatment sitesto receive input reflective of apheresis treatment parameters andclinical effects produced by apheresis treatments, wherein at least oneof said plurality of interconnected computer systems is located at adedicated out-patient apheresis treatment facility; and (b) storingapheresis treatment parameter data and clinical effects data that arereceived from said plurality of interconnected computer systems in acentralized database system, said centralized database system furtherincluding a means for creating a composite patient profile based uponapheresis treatment data that is collected for patients treated at saidplurality of apheresis treatment sites.

A further and related aspect of the invention involves an apheresistreatment data collection and treatment system. Such a system includes:(a) first means for enabling a user to enter information about a patientin a computer database; (b) second means for creating a summary of theinformation entered into the local computer database; (c) third meansfor periodically transmitting the summarized information to a datamanagement system database; (d) fourth means for allowing local users tosearch the data management system database for a specific patientprofile; (e) fifth means for performing data aggregation and analysis onthe data management system database and for producing reports based on asearch criterion; and (f) sixth means for allowing the local users todownload the produced reports. Preferably, the sixth means for allowingenables licensed users to establish the efficacy of RheoTherapy®,Rheopheresis, VasoTherapy, AngioTherapy and like apheresis means.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a patient interaction flow chart schematically illustratingprogress of a patient going through a preferred embodiment of anapheresis treatment process.

FIG. 2 is a continuous improvement flow chart schematically illustratinguse of a preferred embodiment of an apheresis data processing network.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

1. General Description

The present invention relates to methods and apparatus for thetherapeutic, simultaneous depletion of numerous high molecular weightcomponents, particularly rheologically active macromolecules (or “RAMs”)from a patient's plasma. Such rheologically active macromolecules areassociated with a variety of pathological changes which include, forexample, disruptions in microcirculation in affected tissues. RAMscharacteristically exist in several isoforms, have numerous physiologicactions and are capable of promoting the expression of cell-cellreceptors and adhesion molecules. Aside from their primary role inestablishing blood rheology, they also tend to act as procoagulantmolecules and can exhibit behavior like acute phase reactants in thesetting of vascular injury as well. Elevated serum levels of certain ofRAMs have been documented to: (1) cause increases in whole blood andplasma viscosities; (2) promote cell-cell adhesion; (3) disruptintrinsic endothelial cell functions, and (4) cause numerous otherpathologies which can promote various disturbances in themicrocirculation measured as decreases in capillary perfusion leading toultimate end-organ dysfunction or outright failure.

The methods and apparatus of the present invention utilize membranedifferential filtration, and preferably a Rheopheresis® blood filtrationprocess. However, regardless of the particular methods and apparatusutilized, the object of the present invention is the rapid, selectivedepletion or removal of a broad bandwidth of plasma components of highmolecular weight, particularly rheologically active macromolecules.Certain of such macromolecules are known to be involved, directly orindirectly, in various diseases or disorders. However, all of therheologically active macromolecules that circulate as high molecularweight plasma constituents have not yet been identified or linked toparticular diseases or disorders. Preferably, at least two, three, fouror five or more of the rheologically active macromolecules are removedor depleted according to the methods of the present invention. Themethods and apparatus of the present invention generally are effectiveto deplete or remove such macromolecules and components as a class.Thus, levels of known high molecular weight plasma constituents continueto serve as markers for levels of presently unidentified oruncharacterized rheologically active macromolecules and components.

The general steps involved in Rheopheresis® blood filtration involve:(1) treating a patient by the extracorporeal circulation of thepatient's blood, (2) separating first the cellular components from thewhole blood, (3) directing the plasma components fraction thereof to anext filter, (4) sieving the plasma components to remove rheologicallyactive macromolecules therefrom, (5) combining the RAM-depleted plasmawith the patient's cellular components to reconstitute the patient'swhole blood, and (6) returning the reconstituted whole blood to thepatient's body in a continuous fashion in a sterile closed circuit. Theparticular equipment and apparatus utilized and the particular steps,for example, in returning blood components to a patient are not soimportant as the depletion or removal of the high molecular weightcomponents of the plasma and the safe return of the remaining blood andblood components to the patient.

Preferably, such a procedure will be available for use in an averagephysician's in-office practice as a standard therapeutic modality. Morepreferably, such procedures will be conducted in a manner that accessesdata from central data repositories in order to evaluate patients bothas candidates for Rheopheresis® blood filtration and to provideprognostic information to the physician and to provide ongoingmanagement advice to such a physician.

2. Definitions

“Community” means that group of subspecialists and their integralsupport staffs that provide similar medical services and treatsubspecialty-related diseases, such as ophthalmologists treating eyediseases.

“Dedicated out-patient, non-hospital, apheresis treatment facility”means a physical facility that lies outside of a hospital settingdesigned to provide apheresis services to a specific disease group ormedical subspecialty oriented activity.

“Depleting” means that the level of a plasma component, particularlyrheologically active macromolecules, has been removed or reduced in apatient by treatment according to the present invention to a level thatis below, and preferably substantially below, the level of thatcomponent in the patient prior to Rheopheresis® blood filtrationtreatment. More preferably, the therapeutic step of depleting suchcomponent(s) is effective to produce an improvement in a measurableendpoint or an observable clinical improvement in a disease or disorderassociated with the presence of elevated levels of the plasmacomponent(s) in that patient. In a specific embodiment of the presentinvention, the level of such plasma component(s), or of therheologically active macromolecules as a class, has been reduced by atleast about 35-50%, more preferably at least about 50 to 60%, even morepreferably at least about 70%, and most preferably at least about 75% to95% or more.

“Endpoints” means those quantitative and qualitative measurable events,tests, or other definable occurrences that constitute a variable forwhich statistical comparisons can be made at the conclusion of clinicalstudy. By way of example, tests useful to measure such endpoints includethe: (1) “BSCVA” which means best spectacle-corrected visual acuity; (2)“PVSRT” which means Pepper visual skills for reading test; and (3)“VF-14 score” which means a widely accepted standardized and validatedtest in the form of a subjective questionnaire designed to ascertain apatient's evaluation and subjective assessment of their low visioncondition.

“High molecular weight fraction” means those plasma constituents havinga molecular weight greater than about 500,000 Daltons or size of 200 Ådiameter or more.

“Plasma constituents” or “plasma components” means those bloodcomponents in circulation either transported in, dissolved in orsuspended in the serum fraction of whole blood.

“Plasma processing volume” means that volume, usually expressed in cc's,of blood or plasma that is circulated in the extracorporeal circuitduring the course of an apheresis procedure.

“PTCA”—percutaneous translumenal coronary angioplasty, is a mechanicaldilatation procedure whereby a balloon-tipped catheter is threadedthrough a narrowed vessel and inflated to expand the lumen and increaseblood flow.

“Rheologically active macromolecules” or “RAMs” means high molecularweight proteins, lipoproteins and other proteinaceous moietiescirculating in a patient's bloodstream that cause or are commonlyassociated with significant changes in blood rheology, extra-cellularmatrix composition or endothelial cell function that may result inpathological changes in a patient. Such molecules are generallycharacterized as having one or more of the following characteristics:extracellular (located in interstitial space), hydrophilic, mobilizable,soluble in the normal plasma fraction and located within or immediatelyadjacent to a biologic semipermeable membrane that separates thematerial from a proximate blood supply.

“RAM accumulation-deposition diseases” means those disorders or diseasesthat are caused by or associated with elevated plasma levels of RAMs,and which typically involve the accumulation and deposition of suchmacromolecules. The terms “protein accumulation-deposition diseases” and“dysproteinemias” also have been historically applied to theseconditions.

“Rheopheresis® blood filtration” means a specific extracorporeal bloodfiltration or apheresis process whereby a certain bandwidth ofbloodstream constituents, such as the rheologically activemacromolecules, are rapidly removed or substantially depleted throughmembrane differential filtration to remove high molecular weight plasmacomponents. The filtration may also deplete tissue-bound deposits ofRAMs. This filtration also modifies a patient's blood rheology in orderto, among other things, change or improve the pathological state inducedby or associated with the presence of the rheologically activemacromolecules. Such changes may involve: (1) decreasing whole blood andplasma viscosities; (2) down-regulating cell-cell adhesion; (3)improving intrinsic endothelial cell functions, and (4) enhancing bloodflow and perfusion in the microcirculation leading to improvement inend-organ function. As used herein, RheoTherapy® refers to medicalprocedures involving Rheopheresis® blood filtration.

“Type of rheologically active macromolecules” means an individual groupor class of RAM, such as IgM, triglycerides, fibrinogen, etc.

II. Specific Embodiments

A. Rheologically Active Macromolecules

The human blood stream is replete with constituents that regulate boththe hematologic, endothelial and rheologic homeostasis. Some examples ofthese molecules include:

Low Density Lipoprotein (LDL) cholesterols: These atherogeniclipoproteins are currently the subject of intense research. They includeall of the LDL subclasses graded by particle size, lipid composition,and isoform structure. The latest means of measurement include nuclearmagnetic resonance techniques (NMR), as well as enzyme-linkedimmunoselective assay (ELISA) techniques.

Triglycerides (TG): These high molecular weight lipids are another classof lipoprotein and are typically described as particle remnants giventheir dynamic metabolism after production in the liver and elsewhere.These molecular complexes are also measured by NMR and ELISAtechnologies.

Fibrinogen: This blood component protein is widely recognized as apotent risk factor of vascular disease and is involved primarily in theclotting cascade. As with other RAM, fibrinogen has numerous actions andcan be rapidly converted to several forms including: fibrin-D dimers,Fibronectin and other byproducts and acute phase reactants. Thesemolecular complexes are also measured by ELISA and precipitationtechnologies.

Alpha-2 macroglobulin (alpha-2 M) is a proteinase inhibitor whoseprimary biometabolic action is to regulate the production of plasmin.Rheologically, alpha-2 M is the most potent regulator of plasmaviscosity gram for gram in human blood. It is measured by ELISA and gelelectrophoresis techniques.

Lipoprotein A (Lp(a)) is a known cardiovascular risk factor. Lp(a) is aconstituent of Apolipoprotein A1 and serves as the primary ligand forthe cholesterols. It is also measured by NMR and ELISA techniques.

B. Apheresis Equipment

Generally, apheresis equipment is comprised of an extracorporeal bloodpump its constituent tubing and the filtering means. A preferredapparatus is the Plasmatic™ apheresis pump (Apheresis Technologies,Inc.), a three-function microprocessor controlled pumping device thatembodies at least 4 roller blood pumps and the salient alarms, settingcontrols and monitors typical of such apheresis pumps. Secondarily, theOcto 2000® (Apheresis Technologies, Inc. USA; Mesas, GmbH, Germany)provides a multi-functional extracorporeal pumping station providingeight different settings to afford numerous configurations to provideall extracorporeal treatments except dialysis. The preferred filters inthe methods and apparatus of the present invention are the PlasmafloOP-05 (WL) and RheoFilter™ AR 2000®, AR 4000®, and AR 3000® (allmanufactured by Asahi Medical Company, Ltd.). In addition, vascularaccess needles and various vital signs, blood and oxygen monitors areutilized during treatment as is standard in the in-patient apheresissetting.

C. Integrated Apheresis System

In one aspect, the present invention relates to an integrated, medicalsubspecialty-directed, disease-specific apheresis treatment system.

Freestanding Outpatient Apheresis Treatment Facility: One aspect of theapheresis treatment system of the present invention is to employfreestanding, dedicated, outpatient apheresis treatment facilities (orapheresis treatment centers) (see FIGS. 1 and 2) in a network (only oneshown in FIG. 1) for providing apheresis treatment procedures toambulatory patients with RAM accumulation-deposition diseases.Currently, apheresis procedures, where available, are generally carriedout only in hospital settings, in large part due to the historicreimbursement guidelines and the requirement for proximate advanced lifesupport means necessary for the appropriate medical treatment of acutelyill patients in need of apheresis treatment. By performing apheresisprocedures on relatively stable chronically ill patients, theopportunity is afforded to provide those treatments to a broader patientbase and to do so in a more cost-effective manner.

In addition, such a freestanding facility makes it possible to providehighly specialized and individualized treatment to every patient, whilealso providing easier access for the patient to obtain such medicalcare. Many chronically ill patients, especially low vision opthalmologicpatients, experience great difficulty in traveling even short distances,even to the point of not obtaining medical services due to thedifficulty of undergoing such travel. Physically integrating suchabovementioned apheresis treatment into such patients' physician'sexisting practice would provide maximum access to treatment andfollow-up for such patients.

Finally, continued specialized experience in such a medicalsubspecialty-directed, disease-specific apheresis treatment networkformed of freestanding apheresis treatment centers results in a moreconcentrated degree of expertise in the physicians, nurses, and otherpersonnel involved in delivering and following up on the patients'clinical course as such pertains to the present invention. This isespecially true in the assessment of patients' responses to treatmentwhere the clinical outcomes to be determined are far more subtle thanwhether the patient merely survived the illness [treatment]. In oneembodiment, the physician may be located off-site but will beimmediately available by wireless communication, and the facility willprovide a nurse practitioner, a nephrology nurse practitioner orregistered nurse with sufficient supervisory experience.

Although only two freestanding, dedicated, outpatient apheresistreatment facilities 1 are depicted in FIG. 2, it will be appreciated bythose persons skilled in the art that there could actually be a largenumber of such facilities in the network distributed over a large area,even throughout a country, or globally for that matter. Preferably, suchfacilities are anticipated to be linked together in a secure, encryptedcomputerized medical database and outcomes analysis system as describedherein for network and/or Internet distribution of said system-wide datain the preferred embodiment hereof.

Computerized Data Management System: The integrated apheresis treatmentprocess, business delivery method and computer-linked network of thisinvention, preferably to be carried out over such an Internet platform,preferably utilizes a computerized data management subsystem 20 (FIG.2), optimally comprising at least one computer, or CPU, 21 and a storagedevice 24 (actually shown in FIG. 2 as two separate storagedevices—actual-patient-profile and composite-patient-profile storagedevices 24.1 and 24.2—for ease of explanation) as well as all associatedsoftware required to manage and control the system. The computerizeddata management system can be located in one of the apheresis treatmentfacilities 1, but it need not be. In fact, in the preferred embodiment,such a data management system is centralized for ease of maintenance ina separate facility with specialized technicians dedicated to thecontinuous care and maintenance of the computer hardware, integration ofupdated software versions, network troubleshooting, and overall databasesystem management. Therefore, In FIG. 2 the data management system isnot represented as being inside a treatment facility 1 for preferredpurposes hereof.

The data management system 20 provides the capability to: (1) trackapheresis patients through contact, education, evaluation, selection,medical clearance, treatment, referral, and post-treatment evaluationand follow-up processes; (2) provide real-time paperless data entry ofapheresis treatment parameters during apheresis procedures at thetreatment facility; (3) provide central access for real-time remotemonitoring via a secure Internet link of all steps in the apheresistreatment process in the network of freestanding facilities; (4) provideall authorized members of the network with the ability to enter patientdata and to retrieve reports and analyses based on all prior patientstreated (while maintaining the confidentiality of patients' identities)in the network including clinical outcomes, responses to treatment,treatment protocols used, safety analyses, duration of treatmenteffects, etc.; and (5) provide predictive statistical analyses forindividual prospective patients.

The computer system's software architecture is coded in such a way thatit can readily be expanded, even to include other diseases in additionto the AMD example given in the preferred embodiment herein. As will bereadily appreciated by persons skilled in the art, such a system will beconfigured in such a way so as to be easily expandable to readilyprovide similar capabilities of similarly providing information on allapheresis treated patients with any of the diseases mentioned herein,but such a system is not necessarily limited to those diseasesspecifically cited, or necessarily for apheresis treated patients.

The present invention thus provides a computerized data processingsystem for coordinating, managing, directing, entering, accessing andanalyzing all aspects of both local and remote medicalsubspecialty-directed, disease-specific apheresis services anticipatedby the present invention throughout the network.

The computerized data processing system is designed to maintain patientrecords and to serve as a repository for pertinent patient data at boththe local and Internet level. At the local level, licensed users maysupport a secure local database with patient information, retain patientcharts, and access Web reports. At the Internet level, relevant data isstored in the database on a data management system for aggregation,analyses and reporting. Licensed users may access data in the datamanagement system by creating reports and may implement further analysisof reported information to establish the efficacy of Rheopheresis®.

In a preferred embodiment, local users may input data into the dataprocessing system, for each patient, on several transaction forms, whichare accessed from a main switchboard in the data processing system. Themain switchboard displays information about the system and a list bar,among others. The list bar is the primary means of navigating throughthe system. Users may click on icons in the main switchboard to openpatient forms, locate patient records, transfer or download data to andfrom the database in the data management system and/or maintain systemtables. After data has been entered into forms at a local site, the datais periodically uploaded to the database in the data management systemby means of the Internet. Local users may retrieve reports from thelocal database and/or retrieve reports generated from the dataaggregation and analysis that the system performs on the database in thedata management system.

Specifically in a preferred embodiment of the invention, a user entersinformation about a patient at a computer in a local location. At aperiodic predetermined time, a summary of the data, summarized bypre-selected data fields, is transmitted to the data management system'sdatabase. Thereafter, local users may search the data managementsystem's database for a specific patient profile. Alternatively, localusers may use the data management system database to research multiplepatients' profiles. The data processing system performs data aggregationand analysis on the data management system database and producesreports. This enables local users to retrieve information about patientswith similar profiles and maintain patients' confidentiality. The localusers may then download the produced reports to establish the efficacyof rheotheraphy.

Referring to FIG. 2, this data processing, or managing, system optimallyincludes at least one computer (with operating redundancy), or CPU, 21for processing data. The CPU 21 receives actual-patient data from theapheresis treatment facilities 1, as is further described herein,initializes and indexes this data and stores it in at least oneactual-patient-profile storage device 24.1 in the form of profiles foractual patients. Although FIG. 2 shows multiple arrows extending betweenthe CPU 21 and the actual-patient-profile storage device 24.1, one arrowfor each type of data, this is done for illustrative purposes only,because the different types of data could also be e-mailed, scanned, ormultiplexed, between these two components on fewer lines.

The CPU 21 is also capable of processing and analyzing data from theactual-patient profiles of all patients previously treated by themedical subspecialty-directed, disease-specific apheresis providerswithin the network, along with data from all patients currentlyundergoing treatment and creating therefrom composite-patient-profiles,which are shown in FIG. 2 as being stored in at least onecomposite-patient-profile storage device 24.2. It should be understoodby those persons skilled in the art that the various storage devicesshown herein could be single or numerous devices, combined in anyconvenient, or desired manner, however, they are shown separately herefor purposes of illustration. It should also be noted from FIG. 2 thatactual and composite patient profile processing also includes as part ofeach profile, the results 24.1 a and 24.2 a of the treatment, both foractual profiles 24.1 a and composite profiles 24.2 a located, generatedand/or stored within the system.

Patient Recruitment: Referring to FIG. 1, a first step 10 in a treatmentsystem, including an integrated medical subspecialty-directed,disease-specific apheresis treatment process and a business deliverymethod of the present invention, is to locate, primarily by advertisingand by referrals from a treating physicians' referral network,ambulatory, community-dwelling patients with chronic, age-related,degenerative, atherogenic, thrombotic and/or inflammatory diseases, withAMD serving as the prototypical example. These would be patients who arecapable of potentially obtaining clinical benefits from obtaining thedisease-specific apheresis treatments described herein. Locating suchambulatory, community-dwelling patients with such diseases is difficult.It involves the use of numerous coordinated marketing methods,including: direct-to-patient mailings, advertising in various media suchas television, radio, the Internet, and newspapers; anddirect-to-physician marketing within the disease specialty (e.g.,ophthalmologists and optometrists seeking to treat AMD patients) invarious formats, such as attendance and speaking engagements at relatedmedical specialty meetings and seminars and office visits of thereferral network participants.

Preferably, such marketing activities are coordinated and administeredas part of the routine business operations of a treating physician'sestablished medical practice. A significant marketing effort thereforewill be expended by the treating physician recruiting patients alreadywithin his or her practice. However, such activities need not be limitedto the physician's existing patient practice population.

During this awareness/recruitment step 10 (see FIG. 1) as each potentialpatient is located, identifying data (name, social security number, age,condition, diagnoses, clinical symptoms, past medical history, etc.) forthat patient is entered into the CPU 21 (see FIG. 2), which initializesit, indexes it and stores it at 24.1 b as part of that patient's profilein the actual-patient-profile storage device 24.1.

It is therefore another object of the present invention to contemplateextensive marketing efforts to physicians within a pertinentsubspecialty (e.g., ophthalmologists and optometrists seeking to treatAMD patients) to acquaint them with such an apheresis method, asdescribed herein, as a possible therapeutic modality for their patients,and acquaint them with the apheresis means and methods, as describedherein, as a convenient, cost-effective and profit making means forproviding safe and effective therapy for such patients' conditionswithin the context of their existing medical practices.

The present invention contemplates the encouragement of physicians toobtain, from the operations of the business as described herein, thenecessary knowledge and confidence to recommend such medicalsubspecialty-directed, disease-specific apheresis procedures to theirpatients. Or alternatively and preferably, to obtain, from theoperations of the business as described herein, the necessary knowledgeand confidence to establish such a medical subspecialty-directed,disease-specific apheresis treatment facility within their existingpractices to provide such apheresis treatments to their patients as aprofitable enterprise within the context of their own practices. Theprimary challenge of course in conducting such a business is to persuadesuch medical subspecialists (historically unequipped and uneducated asto providing disease-specific apheresis means and methods to theirpatients, e.g., ophthalmologists and optometrists in the case ofpatients with AMD), to provide such apheresis services to such patients.

Patient Qualification, Selection, Clearance and Education: In addition,with each recruited patient's informed consent, he/she is given apreliminary physical examination, preferably at one of the apheresistreatment facilities 1, as part of a qualification step 11. However, anyqualified examiner armed with the specific treatment-qualifyingspecifications and other pertinent information as supplied by theapheresis provider could adequately perform such an examination.(Similar activities are performed during pre-surgical examinations,which are provided by qualified vendors or contractors for surgeonsperforming various procedures.) Qualifying data from this preliminaryphysical examination is entered into the CPU 21, which, in turn,initializes it, indexes it and stores it in the actual-patient-profilestorage device 24.1 at 24.1 c as an additional part of that patient'sactual profile. The qualifying data is initially used for purposes ofqualifying that patient for undergoing medical subspecialty,disease-specific apheresis procedures of this invention. This qualifyingdata includes information which can be derived from such an initialmedical evaluation, and will typically include such items as: (1) pastmedical history; (2) disease specific history; (3) comprehensivephysical examination, including laboratory blood tests that may includeCBC, clinical chemistries, rheology panel, coagulation profile, lipidprofile, immunological profile, and possibly ancillary tests such asEKG, stress tests, renal function, and pulmonary function, etc. asappropriate, as well as information which can be derived from aninterview. In addition, the laboratory analyses of pertinenthemorheologic parameters will receive unique and special attention sincethey will frequently be used as gating factors that will determinewhether a patient shall undergo the apheresis treatment process or not.

Patient Qualification Analysis: At this point in the process, theapheresis provider will access the CPU 21 to analyze the actualpatient's profile compared with a selectable composite patient profile.It will be understood by those skilled in the art that although theactual patient profile, at this point, is limited, or incomplete—becausethis prospective patient has not completed the entire process—thecomposite patient profiles were generated by the CPU 21 using data fromsimilar patients who have completed the entire apheresis treatmentprocess. The composite patient profiles are composites that have beeniteratively generated by the CPU 21 compiled from all of the actualpatient profiles, which have been previously generated and entered intothe network's computer system.

These composite patient profiles are dynamic, in that they arecontinually changing being continuously updated by data entry by allnetwork apheresis providers globally. In fact, the CPU 21 is configuredin such a fashion such that it can analyze the data on an individualizedbasis each time they are needed and generate unique, real-timecustomized analyses on a patient-by-patient basis. The composite patientprofiles include historical clinical outcomes and other pertinentresults 24.2 a, while the actual patient profile for a prospectivepatient who has just qualified for treatment does not yet include anyresults 24.1 a. In any event, once the CPU 21 distills the compositepatient profiles that substantially and favorably compare with theprospective patient's actual patient profile based upon selectablecomparison factors entered by the apheresis provider, it can determine:(1) the probability of treatment success; (2) the potential degree ofanticipated clinical outcomes based upon statistical normograms from ananalysis of the historical patients' profiles of similar patients, and(3) determine the most appropriate initial treatment protocol for theindividual prospective patient about to begin apheresis treatment.

For example, the CPU 21 can determine that: if 800 of 1000previously-treated patients with substantially similar actual patientprofiles were successfully treated and obtained a sufficientlysuccessful clinical outcome while undergoing six apheresis treatments ofa specific nature, then the prospective patient has an 80% chance ofobtaining similar results using the specific six-treatment protocol.Using this information generated by the CPU 21, the patient inconsultation with the apheresis practitioner in the apheresis treatmentfacility 1 can elect or not elect to undergo the procedure, at theselection step 12. Such a real-time prognosticating capability tool hasnever been available to medical practitioners before, and provides asignificant amount of comfort and confidence to such medicalsubspecialists newly providing such apheresis treatments to theirpatients, despite the fact that they have heretofore been historicallyunequipped and uneducated as to providing disease-specific apheresismeans and methods to any patients at all.

Patient Medical Clearance: More particularly, patients are qualified (ordisqualified) and selected (or not selected) as candidates for treatmentby apheresis treatment center staff who, using the data managementsubsystem 20, consider five areas: (1) past medical history; (2) diseasespecific history; (3) comprehensive physical examination, includingblood laboratory tests that may include CBC, clinical chemistries,rheology panel, coagulation profile, lipid profile, immunologicalprofile, and possibly ancillary tests such as EKG, stress tests, renalfunction, and pulmonary function as appropriate; (4) disease specificexamination (e.g., opthalmologic examination); and (5) historicaloutcomes of patients with similar profiles, to firmly establish both theaccuracy of the diagnosis as well as the present extent of the diseaseprocess. Physical examinations and/or laboratory tests may be conductedon site, or may be performed by consultants or qualified off-sitevendors to accomplish this objective, as mentioned above. However, theclinical decision to determine a patient's qualification and suitabilityfor the apheresis treatment herein, under the preferred embodiment ofthis invention, is made by the apheresis treatment center's 1 medicalstaff, in consultation with the prospective patient, prior to theprospective patient undergoing treatment.

Consistency in and completeness of patient assessment and the consistentcollection and review of high quality data are an important part ofpatient identification, evaluation, assessment and clearance fortreatment in the integrated medical subspecialty-directed,disease-specific apheresis treatment process and business deliverymethod of this invention. Therefore, the CPU 21 network system isprogrammed with a number of routines and subroutines that willautomatically alarm and identify data omissions and/or obviouslyerroneous data entries such that the system will accept only the mostaccurate and highest quality data at all times.

As illustrated in FIGS. 1 and 2, patient qualification at step 11, isbased on overall physical condition, and patient selection at step 12,is based on the likelihood that the disease can be ameliorated. Suchdeterminations are continuously improved by iterative feedback frompost-treatment evaluation 18 of historical, composite patient profiles,and from further “completion” of the actual patient profile of theindividual patient as he/she progresses though the multi-treatmentapheresis process of the present invention.

Before selection, as well as during and after treatment, patients andtheir families require extensive education. This education is bestperformed individually and should cover all of the concerns of patientsincluding extensive discussions concerning the sought-after benefits andpotential risks of the apheresis treatment process. In a preferredembodiment herein, dedicated education nurses operating within theapheresis treatment center 1 provide such ongoing education to patientsand their families. The educator initially provides patients withliterature articles and reports of the present clinical experience.Later, the educator can use the CPU 21 to provide a printout of numerousaspects of the therapy, including an individualized report that caninclude the probability for improvement, safety profile and thepotential degree of improvement as described herein. Also, all knownpotential complications and risks, as well as the benefits of thetreatment are described in detail. Finally, prospective patients areprovided with a tour of the apheresis treatment center to acquaint themwith the entire process and to meet the staff. Patients are also giventhe opportunity to meet current patients to obtain their perspectives.Low vision patients are then read aloud an informed consent with theirindividualized treatment protocol to be signed in the presence of awitness. Only then is the prospective patient considered as a candidatefor apheresis treatment.

Patient Pretreatment Preparation: One aspect of patient education thatdirectly impacts and becomes part of the overall therapy relates to thepre-treatment patient preparation regimen. In the days prior to theirfirst apheresis procedure session, a patient is encouraged to engage inlight exercise, such as walking, swimming, mild aerobics, and the like,designed to improve his or her circulation. Also, the patient iscounseled to cease smoking, and is encouraged to adopt a low fat diet,high in green leafy vegetables, the diet being supplemented withvitamins, anti-oxidants (e.g., especially the leutines andxeoxanthanes), minerals (zinc), herbs (e.g., bilberry) as directed bythe educator.

In addition, patients are instructed in venous access preparationincluding applying serial hot packs to the access sites, ball squeezingtechniques and other methods to improve the caliber of the veins, aswell as the blood flow through them. Patients are instructed to eat alarge meal shortly before obtaining their apheresis treatments. Finally,patients are also directed to withhold certain medications prior to theday of treatment. (This would not include, of course, such medicationsas insulin and anti-seizure medicine, and others as directed by theMedical Director of the apheresis center 1.)

Again, data related to these education steps, including diet, exercise,medications, etc. are fed into the CPU 21 by treatment center 1 staff,and the CPU 21, in turn, initializes it, indexes it and stores it in theactual-patient-profile storage device at 24.1 d to become part of thepatient's actual profile. Similarly, since this data was also stored forprevious patients, thereby being incorporated into the historicalcomposite patient profile, the newly updated actual patient's profilecan be compared with the composite patient profiles to see how thesesteps (for example, exercise) affect the probability that the integratedtreatment process and business method of this invention will besuccessful for this patient. Also, using this type of data, thetreatment center 1 staff can tailor the education process to optimizethe probability and the degree of success along with providing realisticexpectations of treatment outcomes to the patient, his or her family,referring physicians and the apheresis staff alike;

Thus, as illustrated in FIG. 1, education 13 is continuously improved byiterative feedback from post-treatment evaluation 18.

The Apheresis Procedure: In the preferred embodiment herein, theapheresis-procedure step 14, and its substeps 15-17, as indicated inFIG. 1, is carried out in one of the apheresis treatment centers 1. Anaspect of the apheresis-procedure step 14 is the design of anindividualized regimen of apheresis treatment whose timing, duration,plasma processing volume and other specific treatment parameters areoptimized for each patient at each treatment, and in whichintra-treatment anticoagulation and monitoring is also optimized. Such aregimen, or protocol, is also entered into the CPU 21 and stored in theactual-patient-profile storage device 24.1 as part of the patient'sprofile at 24.1 d.

As illustrated in FIG. 1, apheresis procedures according to oneembodiment of this invention are each based on “half-sessions” 15 whichare repeated optimally 1 to 4 days later to complete a full session 19.This (full) session is then optimally repeated again after a recoveryinterval of 16±3 days, and preferably about 10±3 days, until apost-treatment evaluation demonstrates significant leveling off of thetreatment effect and/or sufficient amelioration of the symptoms of thedisease state or other clinical endpoint has been achieved.

A half-session 15 includes sequentially: pretreatment readinessevaluation 15 a, with the results thereof being stored in theactual-patient-profile storage device 24.1 at 24.1 e as an additionalpart of the patient's actual patient profile; blood withdrawal,filtration, and replacement 15 b, with parameters thereof being storedin the actual-patient-profile storage device 24.1 at 24.1 f as anadditional part of the patient's actual patient profile; andpost-treatment evaluation and protocol 15 c, with the results thereofbeing stored in the actual-patient-profile storage device 24.1 at 24.1 gas an additional part of the patient's actual patient profile. Ahalf-session 15 also includes continuous vital signs monitoring duringthe course of apheresis treatment, again, results thereof are stored inthe actual-patient-profile storage device 24.1 as an additional part ofthe patient's actual patient profile. As is widely known by thoseskilled in the apheresis arts, such information on patients' responsesand reactions to treatment is important due to the fact that individualpatients have a highly variable tolerance to apheresis treatments.

Subsequent apheresis treatments can be modified to provide patients withan improved experience when such historical information of responses totreatment is provided.

It should be noted that particular areas of the actual patient profilestorage device referred to herein do not necessarily refer to positionlocations, although they are represented in this manner in the drawingsto facilitate understanding. Each piece of data added to a patient'sactual patient profile makes possible more refined instructions from theCPU 21 as to how best to proceed with any further treatments for aparticular patient and as to predictions by the CPU 21 as to thelikelihood of clinical improvement as well as the potential degree ofclinical improvement for the patient. This information is available andbecomes increasingly more accurate as the CPU 21 identifies compositepatient profiles which yet more completely correspond to the data of theactual patient profile as the patient progresses though their treatmentregimen.

A treatment protocol generator for use in a system that endeavors togenerate disease specific treatment protocols based on a patient profileis also contemplated as an embodiment of the invention. The treatmentprotocol generator is comprised of a treatment protocol derivation meansfor analyzing disease specific historical composite patient profiles inorder to derive treatment protocols having enhanced therapeutic effect,a means to identify particular data of a patient profile that will serveto optimize the disease specific apheresis treatment, and a treatmentprotocol generating means for generating a treatment protocol that, whenexecuted, will enable optimization of the therapeutic effect ofapheresis treatment.

Treatment Session Initiation and Interval Timing: One of the mostcritical elements of performing safe and effective serial apheresistreatment is the proper sequencing of serial treatments since excessiveapheresis treatments can deplete essential blood elements and prolongedtreatments may lose their clinical effect. Those blood elements that canbe dangerously depleted by overly aggressive plasmapheresis include: thecoagulation protein factors, albumin, calcium, hematocrit, and proteinsregulating immune function. In practicing the apheresis methods of thepresent invention, it must be kept in mind that although older-agedpatients are typically less resilient than younger patients, if properlyselected as per the above criteria, they are generally in better overallcondition from an apheresis point of view than those younger, butgravely ill patients historically requiring apheresis treatments.Therefore, the standard regimens historically developed for youngerpatients with different diseases are not necessarily applicable in thepresent situation of the present invention.

This is especially true of relatively clinically stable patientssuffering from chronic, age-related, degenerative, atherogenic,thrombotic and/or inflammatory diseases including AMD, who requirespecialized, medical subspecialty-directed, disease-specific managementby treatments that are planned and customized for each individualpatient's unique needs, disease process, and clinical condition.Accordingly, apheresis treatment is conducted only after thepre-treatment readiness evaluation 15 a is performed immediately priorto each treatment. This evaluation includes an abbreviated interimhistory a brief physical examination, and the evaluation of laboratorytests including calcium, ACT coagulation, hematocrit, and such othertests as may be suggested by patient's condition and previous responseto treatment experience. In addition, prior to each treatment, patientsare assessed for changes in weight, plasma volume, and state ofhydration. These factors, as well as the patient's demonstratedtolerance to prior apheresis procedures, will factor into both thedecision whether to proceed with apheresis treatment at all, and if so,what the target plasma volume percentage for that day's treatment willbe. Again, this data is fed into the CPU 21 to become part of thepatient's actual profile, and decisions as to how or if to proceed arebased on the CPU's 21 comparison of this updated profile with thecomposite patient profiles. Of particular note, it is not the intentionof the computer system of the present invention to supersede theclinical decision-making of the apheresis providers and medical staff ofthe facility 1. The computer system is provided to be merely anefficient tool, designed to assist clinicians in making the numerousdeterminations relating to the care and treatment of their patients. Theultimate decisions concerning the treatment of said patients herein,shall remain the exclusive domain and responsibility of the providers ofthe patient's care. Their clinical acumen and expertise will alwaysprovide the basis of any and all treatment-related decisions made.

Intra-treatment Evaluation and Monitoring: In a similar manner,continuous and careful evaluation of a patient's clinical symptomatologyduring the multi-treatment apheresis protocols guides the duration ofthe apheresis treatments for patients, again based on feedback from theCPU 21. The objective of any individual apheresis treatment of thepresent invention as it is applied to said patients herein, is toprocess 100% plus or minus 20% of such a patient's plasma volume, with100% being considered the usual target, and about 200% being processedin any one week period of time. However, such a patient must remainclinically stable in the judgment of the apheresis provider, throughoutthe apheresis procedure in order to maintain the safety marginsnecessary to continue the procedure. Therefore, the preferred embodimentof the present invention provides for continuous measurement of pulse,blood pressure and oxygen saturation, and regular, intermittentmeasurement of temperature and respiration throughout the apheresisprocedure and during one hour afterwards in a recovery monitoringenvironment. Adverse events in apheresis procedures are rare, but canoccur. Continuous patient monitoring, combined with good clinicaljudgment offer the best means to provide said apheresis treatmentdescribed herein safely and effectively. Fortunately, the expression ofadverse events typically evolve slowly and can be immediately halted andreversed with suspension of the treatment process.

D. Preferred Design of a Network System

A preferred network system is designed to maintain patient records andto serve as a repository for pertinent patient data at both the localand Internet level. This example illustrates the development of such asystem related, for example, to the treatment of patients with oculardisease. At the local level, licensed users will be able to support asecure database for patient information, retain patient charts, andaccess web reports. Visual Basic will be used as a front end to a JetAccess backend. At the Internet level, relevant data will be stored in acentral location using SQL for aggregation and reporting. Licensed userswill have access to this data through the use of reporting. Licensedusers may implement further analysis of report information to establishthe efficacy of RheoTherapy®.

The system accomplishes these tasks by capturing data that the userinputs on several transaction forms for each patient. To access theseforms, the user is presented with a Main Switchboard upon launching theapplication. The Main Switchboard displays information about the systemand site licensee as well as a List Bar. The Main Switchboard has asimilar look and intuitiveness as Microsoft Outlook or Outlook Express.The List Bar is the primary means of navigation throughout the system.Icons are exposed which the user clicks to open patient forms, locatepatient records, transfer or download data or to maintain the systemtables. The patient forms are the entry points for data storage. Theseforms are organized into eight categories that are displayed in a TreeView. The Tree View presents items in a hierarchical list resemblingMicrosoft Windows Explorer. Subcategories are located underneath thecategories in an outline style to further enhance the ease of userinteraction.

The form categories include General Patient Information, MedicalProviders, Patient Check List, History & Physical, Ocular Information,Treatments, Lab Results and Documents. The comprehensive areas ofHistory & Physical, Ocular Information, and Treatments have a series offorms associated with specific areas of importance for each category.After the data has been gathered at the local site, the information willbe periodically uploaded to the central repository by means of theInternet. In addition to local database reports, users will be able toretrieve reports generated from the data aggregation and analysis thatthe system performs on the central database. Specific local reportsinclude the Patient Treatment Summary Report and the Patient ResponseReport, local and Internet Reports will be the Overall ImprovementReport, Period Summary Report, QI Report and an Internet only PatientPrognostication Report. The Patient Prognostication Report is furtherdivided into Visual Acuity Assessment, Subjective QuestionnaireAssessment and Objective Assessment.

Specifically, the General Patient Information form contains thepatient's name and address as well as related information including thenext of kin and emergency contracts. The patient information may besearched through the use of a Patient Finder. The finder examines thedatabase for matches to searchable fields that the user is able toselect from a list. Boolean operators such as greater than, less than,equal to, and between give the user greater flexibility to narrow thescope of their inquiry. Further selecting a Criteria to search fieldupon by using a single letter of the alphabet, the first few letters ofa name, or a given date, for example, provides additional versatilityfor the user to quickly locate the specific information they are tryingto retrieve.

The Medical Providers record contains the names of Family Physicians,Ophthalmologists, Optometrists, and others that have contributed to thepatient's overall medical care as well as eye care. This is also asearchable set of records where the users can locate specificinformation regarding the Medical Provider's location, phone number, andspecialty. Furthermore, the user will be able to identify if the medicalprovider is designated for the patient's follow-up care. Thisinformation may be searched through the use of the Medical ProviderFinder. This finder performs the same as the Patient Finder describedabove. The two finders are specific for either the patient or themedical provider.

The Patient Check List is a repository of significant dates which arerelated to the patient's medical information and treatment schedule.Dates regarding the first and last contact with the patient, when theout-of-town mailer was sent, consent forms signed, medical and labrecords received, and dates of when medical, nutritional and educationalinstruction was presented to patients are maintained. The system willautomatically generate and update several of these dates specifically inregards to treatment dates and dates of first and last contact. Theusers will enter in the other dates as applicable.

The information gathered regarding the patient's History and Physical issubdivided into six sections. The History & Physical General Informationform includes data concerning the patient's eye color, overall physicalcondition, overall mental status, ethnicity or race, date since theonset of the disease and allergies that they might have. The Historysection contains information regarding the patients' drinking andsmoking habits, social habits, and specific medical history. TheMedical.

Provider uses the Physical portion of the History and Physical to placedetails about the patient's specific physical findings at the time ofexamination. The specific areas 25 include the head, eye, ears, nose,throat, neck, and lungs. The Family History Medical record containsinformation of familial disorders and diseases. The form FamilyGenealogy is used to record if relatives are living or deceased and ifdeceased, the age of death. The last section, Home Medications, is wheredetails are placed regarding the medications the patient takes at homeas well as the dosage, frequency, and route of administration of thesemedications.

The Ocular Information is entered in three specific areas comprised ofPrior History, Diagnostic Exams and Eye Exams. The Prior History form issubdivided into Physical Findings, Symptoms, and Diagnosis sections. Allthree sections provide for the user to select detailed entries from alist for a physical finding, symptoms or diagnosis. The Diagnosis may beentered by either ICD9 code or by selecting a description. Each sectionprovides entry fields for which eye was examined and the date ofexamination. The Diagnostic Exams forms is used to input Prior Tests andPrior Treatment the patient may have received for ocular care. Dataentries are again selected from a list and fields are provided to inputwhich eye was examined and the date of examination. An Eye Exam Listform is viewable to display a chronicle of previous eye exams thepatient has had and then to quickly locate the associated record. TheEye Exam form itself allows for input of BSCVA, Visual Acuity,Subdivision, Contrast Sensitivity, IOP, Refraction Sphere, RefractionCylinder, Refraction Axis, Pepper Test and the results of the ColorTest. The form is partitioned into two panels. One panel is for righteye data (OD) and the other panel for left eye data (OS).

The Treatments section consists of several forms for user inputconcerning information relevant to medical orders, treatment details,patient questionnaire, and quality insurance. A Treatment List form isviewable to quickly display a chronicle of previous treatments thepatient has had to date and then to quickly locate the associatedrecords. Furthermore, a Medical Provider may initiate a treatment regimefor a new patient or add a treatment for an existing patient from thisform. A record for Standing Orders is placed at the top of the hierarchybeneath the Treatments category. The Standing Orders are typicallydefault orders that the Medical Provider will supply should specificevents or medical responses occur with regard to all of their patients'treatments. Displayed below the Standing Orders are icons to indicatethe dates that treatments were initiated for a patient. If a treatmenthad to be canceled for medical reasons, this date will be designatedwith a distinct icon.

For each treatment date there is an associated form for RT Orders,Medication Orders, Discharge Instructions, Questionnaire, Flow Sheet 1,Flow Sheet 2, and Lot Tracking. The RT Orders record contains thePretreatment Orders section for orders such as laboratory blood analysisand the Treatment Orders section for orders pertinent to fluid volumemaintenance, anticoagulants and patient monitoring. The MedicationOrders form records treatment data relevant to fluid replacement andanticoagulants. The Discharge Instructions provide patient informationfor post treatment home care. To document patient response andimprovement as the RheoTherapy® treatment progresses, a Questionnaireform is provided. Here changes in the patient's mental and physicalconditions are recorded. Flow Sheet 1 will retain specific patientinformation such as pre and post treatment vital signs and specificinfusion machine data including machine serial numbers. Flow Sheet 2will be for recording patient and machine conditions at timed intervalsover the course of the treatment. Additionally, the total volume removedand the total volume replaced are reported on Flow Sheet 2. The LotTracking form is used to input applicable information for supply itemsregarding lot numbers, manufacturers and expiration dates of materials.

The Lab Results form is used to report the patient's blood laboratoryanalysis at different stages of treatment. A Lab Results List form isviewable to display a chronicle of previous lab results the patient hashad and then to quickly locate the associate record specific laboratorytests may be grouped into a category referred to as Rheofactors.Rheofactors are laboratory tests that have been associated with specificpatient responses as a result of RheoTherapy®. These tests include TotalCholesterol, Fibrinogen, HDL and IgA analysis.

Word processing documents that are associated with individual patientsmay be stored in the local database. These files are located under theDocuments category. A Documents List form is viewable to display achronicle of word processor files that have been retained for thepatient and to quickly locate the associated record. Files may be addedto or deleted from the patient's records from this form. Data gatheredin the forms will be uploaded to a central repository periodically bythe user. If after a given period the user has not uploaded the data,the system will prompt them to perform this simple procedure. with asingle mouse click, the data is retrieved from the local Access databaseand passed through the Internet to the central repository where theInternet Information Server and Microsoft Transaction Server seamlesslycoordinate to store the data on a SQL Server. After the data has beentransferred to the central repository, the user may disconnect from theInternet. All of the data processing necessary takes place without userintervention or loss of valuable time. In a similar fashion, reportswill be produced at the central repository and returned to the user.

Reports from the system database may be generated at either the local orthe Internet level. The Patient Treatment Summary Report and the PatientResponse Report will be local reports. The Patient Treatment SummaryReport will present the Treatment Number, Date and Total Volume Removedfor each treatment for a given patient. The Patient Response Report willdisplay an analysis of how the patient's eyes have responded toRheoTherapy® treatment based upon a comparison of eye examinations andquestionnaires from pre treatment and post treatment data.

Three reports may be generated at the local or Internet level and willconsist of the Overall Improvement Report, Period Summary Report and theQI Report. The Overall Improvement Report will present the number ofEyes Treated and the Percent Improved for nine predetermined diseases.Again, a pre treatment and post treatment analysis of the data will beperformed. The Period Summary Report will summarize in chart form thetreatments administered with respect to the Total Number of PatientsTreated and the Total Number of Treatments Provided for a set timePeriod. Furthermore, for this time period, the Total Number of PatientsTreated for each of nine predetermined diseases will also be reported ina table. The QI Report will be used to summarize the number of adverseevents that occurred during the treatment of a patient. The PatientPrognostication Report is only an Internet report. The local databasedoes not contain sufficient information to produce a meaningful report.This report is utilized to provide the patient with informationregarding how other patients with similar History, Diagnosis andRheologic Factors have responded to RheoTherapy®. The PatientPrognostication Report is generated from data the system retrieves fromthe central database repository of all records for all patients. Otherpatients are matched to a potential patient's profile based uponspecific criteria and data is then aggregated and analyzed to generate apossible treatment prognostication.

By providing both local and Internet database support, licensed users ofthe system will be able to maintain patient charts and records as wellas contribute to and benefit from data aggregation that results in acompendium of information relating to the effects and benefits ofRheoTherapy®.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following workingexamples therefore, specifically point out preferred embodiments of thepresent invention, and are not to be construed as limiting in any waythe remainder of the disclosure.

EXAMPLES Example 1 Example of an Apheresis Session

During an apheresis session, a patient reclines in a comfortable blooddonation chair and intravenous (IV) lines are introduced, one into theantecubital vein of each of his or her forearms. (Single arm accessmethods and central lines or PIC lines are also possible but are lessdesirable). The IV catheters are either 17 gauge steel needles or 14gauge plastic IV catheters, depending upon the caliber and location ofthe blood vessels to be cannulated. Blood is optimally withdrawn andcirculated from the patient at a rate in the range of 75 to 150 cc/min.The time to complete an apheresis procedure of this invention variesfrom patient to patient, and from day to day depending upon numerousvariables. However, the average time required to process 80% to 120% ofa typical patient's plasma volume, usually requires 1.5 to 2.5 hours forthe average AMD patient, who serves as the prototypical example.

The blood is pumped out of the body via an extracorporeal circuit,through the apheresis pumping equipment, including any membranedifferential filters, and then back into the body. Usually only about250 cc of a patient's blood is located within the extracorporeal circuittubing at any given time during the procedure. As will be known topersons skilled in the art, there are several types of apheresisprocedures that can be used to alter the blood's rheology. Each type hasits benefits and drawbacks.

Plasma exchange, as practiced in the context of the present invention,can be conducted using replacement solutions containing primarily 5%human albumin mixed with saline and Hespan®; selective adsorption isconducted using a tryptophan-polyvinyl alcohol adsorber (TR-350 fromAsahi Medical), and membrane differential filtration is performed usingthe paired hollow fiber filters, e.g. the RheoFilter AR2000 and theOP-05 plasma separator. In each case, the plasma separation deviceoperates to divide the whole blood's cellular fraction from the plasmafraction. In plasma exchange, the plasma is iteratively removed viasequential filtering steps with a centrifuge or hollow fiber filterdevice. The plasma portion is discarded and can be replaced with asolution of saline/HES and 5% human albumin. The targeted high molecularweight proteins are depleted but so are the other plasma components.Therefore, the efficiency of this system is comparatively less than thatof the MDF system. In addition, the costs to perform plasma exchange arealso significantly higher than MDF filtration.

Immune adsorption is also usable but sensitization to column componentsprovides a significant patient safety risk compared to MDF systems.Therefore, it has been determined that the MDF system is both safer,easier, more efficient, faster and less expensive that any otheravailable system in the market today, and is therefore the apheresistreatment system of choice for the performance of the present invention.

As described herein, the MDF system has been shown to significantlyreduce plasma concentrations of numerous circulating macromolecules,including alpha-2 macroglobulin, triglycerides, the cholesterolsuperfamily of beta-lipoproteins, various immunoglobulins, fibrinogen,AGE-modified lipoproteins, and the like.

Persons skilled in the art will know to administer anticoagulants, suchas heparin injected as a bolus prior to therapy, followed by acontinuous infusion, and ACD-A (anticoagulant citrate diacetate)continuously infused at a ratio of 1:16 during the course of treatment.ACD-A is the generally preferred anticoagulant of choice in conventionalapheresis for extracorporeal apheresis circuits, since it does notpromote systemic anticoagulation effects in the patients being treated.When ACD-A is used, it is customarily accompanied by continuous infusionand/or ingestion of calcium to prevent systemic depletion of calciumion, which can lead to numerous deleterious effects (myocardialexcitability, muscular fasciculations and parasthesias).

Heparin Sodium (both low and high molecular weight versions) can be usedin place of ACD-A, and is the non-obvious yet preferred anticoagulant ofchoice in the present invention because of heparin's actions within apatient's systemic circulation as well as throughout the extracorporealcircuit, and over-heparinization can lead to excessive bleeding in apatient. However, if over-heparinization does occur, such effects can besafely and quickly neutralized with the administration of medicationssuch as Vitamin K infused intravenously.

In the preferred embodiment of the present invention, Heparin Sodium isprovided as an initial bolus, then as a continuous infusion determinedby the standardized formula involving the patient's weight. Generallyless than a total of 15,000 IU (international units) of Heparin Sodiumare necessary to maintain appropriate levels of anticoagulationthroughout the apheresis procedure of the present invention. Theanticoagulation status of the patient is monitored frequently (ACT test)throughout the procedure and afterwards in order to ensure appropriateanticoagulation within the established limits of safety forextracorporeal circuit therapies, e.g., cardiac bypass machine circuits,etc.

A preferred embodiment of the present invention provides for continuousmeasurement of pulse, blood pressure, and oxygen saturation, as well asintermittent measurement of temperature and respiration. In addition, itis preferred that the patient be continuously connected to an EKGmonitor capable of automatically detecting and documenting anomalouscardiac rhythms for further evaluation. Apheresis in the presentinvention is complete when approximately 80% to 120% of a patient'splasma volume has been treated in a single session. However, anydeterioration of the patient's clinical status in terms of pulse, bloodpressure, oxygen saturation, temperature, respiration, or heartfunction, or the treatment nurse's ongoing clinical assessment, mayresult in premature termination of the procedure prior to reaching thistarget.

After treatment, the patient is monitored while resting forapproximately an hour, consuming fluids and a snack. If uneventful, onlythen is the patient discharged. Patients are instructed not to drive for24 hours.

As illustrated in FIG. 1, and as stated above, post-treatment evaluationis the foundation of continuous improvement in the integrated apheresistreatment process and business method and business method of delivery ofthis invention.

Rheopheresis® treatments preferably are administered in a period rangingfrom about one day to about ten days, such that at least about 200% of apatient's plasma is processed during about a one-week period of time.Persons skilled in the art will understand that treatment provided onlyonce per month likely will be insufficient to improve clinical outcomesand that treatments provided on a daily basis or even up to about twotimes per week may be debilitating to a patient in the sense that theydeplete excessive amounts of high molecular weight plasma components.However, relatively more frequent Rheopheresis® blood filtrationtreatments would be appropriate in acute situations, as discussed below.TABLE 1 shows the “Mean Elimination Kinetics of the RheoFilter MDFSystem” Mean Elimination Kinetics of the VasoFilter MDF System* MembraneFiltration % Parameter Brunner¹ JJA² Utah³ Tauch⁴ SBP⁵ Gode⁶ Mass⁷Proteins/Lipoproteins Total Protein −19 −13 −27 −15 −23 −23 Albumin −4−2 −28 Total Cholesterol −53 −76 −46 −44 −53 −54 Triglycerides +2 −62−58 −34 LDL-Cholesterol −67 −100 −66 −49 −57 −60 HDL-Cholesterol −38 −15−29 −31 −42 −43 VLDL-Cholesterol −6 −95 −55 Lp(a) −87 Apolipoprotein A₁−19 Apolipoprotein B-100 −100 Plasmin −20 Alpha-2 Macroglobulin −70 −80IgG −34 −17 −32 IgA −41 −40 −39 IgM −67 −91 −58 −36 C3 −31 C4 −42Hematological Erythrocytes −4 +3 Leukocytes +2 +93 Platelets −6 −12 +1Hemoglobin −6 +3 Hematocrit −3 +4 +2 MCV +1 0 Coagulation Fibrinogen −47−57 −60 −56 −54 −55 Fibronectin −74 PT −7 PTT 0 TT −7 Antithrombin III−13 Rheology Plasma Viscosity −15 Whole Blood Viscosity −16 ErythrocyteAggregation −55*Plasmaflo ® OP-05W, and RheoFilter ® AR 2000, post- & pre-treatmentserum concentration.¹Brunner et al., J. Artif. Organs (1995) 18, 794-798.²Sonntag et al., Jpn. J. Apheresis (1997) 16, 26-30.³Unpublished data from the University of Utah study (1998).⁴Tauchert et al., Jpn. J. Apheresis (1997) 16, 34-37.⁵Saito, International Society of Blood Purification, Nagoya (1900)81-82.⁶Godehardt et al., Prevention of Coronary Heart Disease InternationalSymposium, Munich (1992) 208-2127.⁷Messner et al., Prevention of Coronary Heart Disease InternationalSymposium, Munich (1992) 204-207.

Table 1 is a composite presentation of research in the field measuringthe ability of the Rheopheresis® system to deplete certain RAMs. Bloodsamples were drawn at different post-treatment intervals and provideonly a trend analysis as opposed to a specific statement concerning theprecise depletion capability. Of note, it is important to understandthat every patient has different distribution kinetics, and theirre-equilibration times vary significantly. Therefore, it is critical tomeasure these profiles with each patient at the suggested intervals sothat the Rheopheresis® practitioner can establish the optimal treatmentprocessing volume and inter-treatment interval for each patient on anindividualized basis. Appropriate treatment dosing and scheduling mustbe tailored to each patient and to each disease process and the generalprotocol developed. Otherwise excessive RAM depletion can occur,resulting in immunocompromised patients, over-anticoagulation orunder-treatment, thus reducing safety and/or clinical effectiveness.Table 1 shows the differences in the averages that were observed inrelatively large numbers of samples. Individual depletion ranges canvary significantly from the means analysis.

Example 2 Treatment of AMD

The skilled artisan will understand that AMD serves as the prototypicalmodel for chronic, age-related, degenerative, atherogenic, thrombotic orinflammatory diseases, especially those manifesting disturbances ofblood rheology, of which other examples are mentioned above. The body ofwork, discussed above, by Brunner, Berrouschot and others generallysupports the basis of the present invention that the depletion and/orremoval of these blood proteins leads to numerous interrelatedalterations in blood rheology, along with their secondary and tertiaryeffects. While these effects may be more generally distributed, in AMDthe changes appear to promote a return to function in ostensiblysenescent but otherwise viable cells in the posterior retina.

Drs. Swartz and Rabetoy (publication pending) conducted research at theUniversity of Utah that demonstrated that select patients with Dry AMDwho demonstrated significant improvement in their visual function afterRheopheresis® blood filtration had elevated pre-treatment baseline serumconcentrations of certain rheologic protein markers. Data from thisstudy is discussed below. A significant distinction between thetherapeutic protocols of the present invention and others, e.g., theBrunner and Berrouschot protocols, is the length of the interval betweensubsequent even-numbered treatments. In the Brunner study, a 30-dayinterval was selected. Berrouschot was excessively aggressive providing12 to 24 hour intervals. Brunner's interval was selected based upon thereimbursement policies in place at the German hospital system where theresearch was conducted and was not based on any scientific correlationof or regard for the maximization of therapeutic effects or rheologickinetics. Berrouschot's protocol was designed to reduce acutemacrovessel occlusion. The present inventor has discovered,unexpectedly, that this protocol feature can be altered to achievedramatically improved clinical outcomes in diseases of the typedescribed above that primarily involve the microcirculation as thetherapeutic target of action.

Drs. Swartz and Rabetoy evaluated 30 patients with non-exudative AMDcharacterized by numerous large soft drusen. The patients wererandomized into three groups of ten patients each: (1) an activetreatment group; (2) a circuit (“sham column”) group; and (3) ano-treatment control group. MDF treatments were performed with the Asahifilter system as described above. Apheresis patients (MDF and circuit)were evaluated over approximately 18 to 20 weeks while receiving tenprotocol apheresis treatments. All patients underwent a battery oflaboratory and opthalmologic tests. “Improved vision” was defined asconsistent, significant, correlated improvement in at least three of thefollowing four visual assessment parameters: (1) 2.5 lines of BSCVA(best spectacle-corrected visual acuity) improvement in the Study Eye;(2) 2.5 lines of BSCVA improvement in both eyes; (3)>20% increase inPVSRT (Pepper Visual Skills for Reading Test) scores in at least oneeye; and (4)>20% improvement in the VF-14 Questionnaire© scores. By thisstrict definition, “improved vision” occurred in four of the 30 patientsstudied. All four of the patients who improved were in the MDF treatmentgroup. This represents 40% of that group, to a statistical power ofp=0.023.

Within the MDF Treatment Group, a positive correlation was independentlydemonstrated between post-treatment “improved vision” and baseline serumlevels of four rheologic markers identified as: total cholesterol, IgA,fibrinogen, and HDL cholesterol, (the latter being recognized as asubstance known to be a potent vaso-protective agent primarily involvedin reverse cholesterol transport). Higher baseline levels of any one ofthese factors were positively correlated with both the likelihood ofimprovement as well as the degree of associated total, post-treatmentBSCVA line change. Five patients in the MDF treatment group presentedwith elevated baseline values of at least three of these four rheologicmarkers. Four of these five patients (80%) demonstrated “improvedvision” exhibiting total increases in ETDRS line change (StudyEye+Fellow Eye) of 5.5, 6.0, 8.0, and 8.5 respectively. All four ofthese patients with “improved vision” presented with elevated baselineconcentrations in all four (100%) of the rheologic markers mentionedabove. This was considered to be highly significant.

The following case studies demonstrate the results of Rheopheresis®treatments in seven different patients with different types of AMD. Thepatients in these case studies were treated under protocols consistentwith the foregoing description of the invention.

Case Study #1

Patient #1 was a sixty-six (66) year old female referred by her retinaspecialist in for consideration of RheoTherapy® for her AMD. She wasfirst seen by this retina specialist on Apr. 4, 1997. At that time shecomplained of decreased vision in the right eye with metamorphopsia. Atthat time her vision was 20/50 OD and 20/50 OS. She had cataracts inboth eyes. The fundus exam revealed a pigment epithelial detachment ODand a possible net. A fluorescein angiogram showed a PED OD and dry AMDOS and indocyanine green angiogram showed a sub fovial plaque. When shereturned Dec. 3, 1997, her vision had deteriorated; she was havingdifficulty ready newspapers. At that time visual acuity was 20/200 ODand 20/30 OS. Fluorescein angiogram revealed a PED with no definitefocal net. Left eye appeared normal. The retina specialist referred herfor RheoTherapy® at that time. She had treatments on Jan. 6, 1998, Jan.8, 1998, Jan. 19, 1998, Jan. 21, 1998, Feb. 17, 1998 and Feb. 19, 1998.She tolerated all these treatments well. After her first treatment shehad noted significant improvement. She was more comfortable driving andwas able to sit farther away from the television. She also notedimprovement in her amsler grid and could see tiny threads on hermattress. She was very pleased with her therapy. She continued toimprove with subsequent treatments and after four treatments was able toread with her bedside lamp for three to four hours at a time. Thegrayness had resolved and the amsler grid was clear. She returned to seeher retina specialist on Feb. 25, 1998. She told him that her vision hadimproved but that she was still having difficulty with reading andwatching television. At that time her vision had improved to 20/50 ODand 20/30 OS. She still had some metamorphopsia OD. Her fundus examshowed a PED but it had decreased in size on exam and the fluoresceinangiogram showed mottled leaking but no evidence of definite PED. Shehas subsequently had two more treatments and is awaiting a follow-upvisit with her retina specialist who has referred more patients to us.

Case Study #2

Patient #2 was a fifty-five (55) year old male referred by hisoptometrist for treatment of AMD. He was amblyopic and is blinded in hisleft eye. He was found to have dry AMD involving his right eye severalyears ago. His vision had worsened from 20/15 to 20/40. Patient #2 beganhis treatments Jan. 5, 1998 and had a second treatment on Jan. 7, 1998.On Jan. 13, 1998 he reported that he had returned to his optometrist andhis vision had improved from 20/40 to 20/25 after only two treatments.His cholesterol had also dropped from 250 to 191. By the time he arrivedfor his third treatment on Jan. 26, 1998, he said his vision had alreadyimproved to 20/20. He was ecstatic. His fourth treatment was given onJan. 28, 1998. He was seen by his primary optometrist on Jan. 30, 1998.The optometrist was very pleased with the results of RheoTherapy®treatments. As a result of the six (6) RheoTherapy® treatments, hisvisual acuity in his right eye improved from 20/40−2 to 20/20−1. Theoptometrist also noticed that the area around his macula had a bettercolor and the scattered black pigment was more defined. On Feb. 3, 1998,he returned to see a retina specialist who had previously given him nohope. The specialist reported that the vision in the OD was 20/20. Whatthe retina specialist found most significant was that the low contrasttesting done in October, 1997 was 20/100 in the right eye and it hadimproved to 20/50−1 by Feb. 3, 1998 after only four RheoTherapy®treatments. The retina specialist also reported that Patient #2mentioned improved vision, brighter color sensation and improvedcontrast after the first treatment. He also had an increased energysensation and improved contrast after the first treatment. He also hadan increased energy level. He subsequently had treatments on Feb. 23,1998 and Feb. 25, 1998.

Case Study #3

Patient #3 was a sixty-four (64) year old male with a long history ofcentral serous retinopathy. He has been seen multiple times in the pastby a world renowned expert on macular disease. He had multiple lasertreatments by this expert. His vision continued to deteriorate to thepoint where he could no longer function in his employment as aprofessional engineer. Visual acuity on Apr. 12, 1996 was 20/200 OD and6/200 OS. He had his first RheoTherapy® treatments on Mar. 14, 1997 andMar. 17, 1997. Repeat exam by the local retina specialist showed visualacuity of 20/50 OD. He could count fingers at two feet OS. He has hadanother seven (7) treatments. On Sep. 11, 1997, after a total of eight(8) treatments, visual acuity fluctuated between 20/30 and 20/40 OD andwas 20/200 OS. Patient #3 stated that since his last visit he has hadanother eye exam and visual acuity is now 20/20 near vision and 20/30distant vision. He was extremely pleased with his improvement because heis again able to function as an engineer. He was also again able toproduce and interpret engineering drawings and drive an automobile.

Case Study #4

Patient #4 was a sixty-three (63) year old male who was diagnosed ashaving AMD by exam on Oct. 2, 1997. At that time, visual acuity was20/25 OD and 20/40 OS. He had neovascularization in his right eye and amacular detachment in the left. On the fluorescein angiogram thesubretinal neovascularization OD leaked slowly. His ophthalmologistoffered no treatment since the leakage was in the area of the fovea. Areport examination by the same physician on Oct. 23, 1997 revealedvisual acuity of 20/25 OD and 20/60 DOS. On Nov. 13, 1997 visual acuitywas 20/20 OD and had deteriorated to 20/100 OS. His ophthalmologistsuggested RheoTherapy® treatment. After two (2) treatments he noticed asignificant improvement and was reading with no difficulty. After four(4) treatments, he reported further improvement. Prior to treatment, hewas unable to distinguish his cattle from each other and could notdistinguish their shapes in the pasture. After four (4) treatments hewas again able to do so which is very significant because he is a cattlerancher. He was again able to grade the cattle morphology to determinenutritional status. He previously was unable to distinguish anythingwith his left eye, and after four (4) treatments he was able to readlarge print with his left eye. A fluorescein angiogram done by thereferring physician after four (4) treatments was reported as showingsignificant improvement. Patient #4 received a total of eight (8)treatments and now reported his vision as being 20/15 OD and 20/40 OSfollowing those treatments.

Case Study #5

Patient #5 was a fifty-two (52) year old male with a history of familialmacular drusen OU. Visual acuity was 20/300 OD and 20/200 OS Sep. 13,1994. Fluorescein angiogram showed no neovascularization. At that timehis ophthalmologist gave him no options for treatment. Best visualacuity on May 23, 1997 was 20/400 OD and 20/200 OS. After four (4)RheoTherapy® treatments, he still had distortion of his vision but hisvision adjusted more quickly after exposure to bright light than it hadpreviously. A repeat visual exam after two (2) treatments revealed avisual acuity of 20/70 OD and 20/60 OS.

Case Study #6

Patient #6 was a seventy-three (73) year old male with a long history ofAMD. He is blind in his left eye due to wet AMD. He has dry AMD in hisright eye. Visual acuity OD was 20/50. Fundus exam by his retinaspecialist prior to treatment revealed dry macular degeneration and afew areas of chorioretinal atrophy in the right eye. He has undergonesix (6) RheoTherapy® treatments. Between his first and secondtreatments, he had transient improvement in his vision in that objectsappeared brighter. He then noticed no improvement through his fourthtreatment. After no improvement with four (4) treatments he considereddiscontinuing therapy but decided to continue therapy for two (2) moretreatments because so many people that had treatments when he did hadnoticed improvement. After his fifth (5) treatment he stated that hethought he could see golf balls better. His wife reported that he is nowable to read standard sized print without a magnifying glass. Hepreviously needed a magnifying glass. He is also able to read letters onchart moving his eyes from left to right where previously he had toshift his eyes left to right to “catch” all of the letters. He alsoreports significantly increased intensity of red on the traffic light.He previously stated he had to be told by his wife that the light wasred.

Case Stud #7

Patient #7 was a seventy-four year old male with a long history of dryAMD OD and wet AMD OS. Visual acuity was 20/400 OD and 20/30 OS on Aug.29, 1995. On Dec. 17, 1997 visual acuity was hand motion OD and 20/400OS. Patient #7 stated that his doctors offered him essentially notreatment. He had tried multiple low vision aids without any significantsuccess. Despite laser photocoagulation OS in 1995, he had regrowth ofthe abnormal blood vessels and could not undergo repeat lasercoagulation without increasing the size of the central blind spot. Aftereight RheoTherapy® treatments, he reports that the amount of light hedetects continues to increase. He is now able to recognize faces whenlooking straight at the person. He was not able to do that previously.He reported that the blind spot in his left eye had fragmented anddiminished in size and the wavy lines have straightened.

The use and general benefits of Rheopheresis® blood filtration for thetreatment of AMD also is described in Davis et al., in Optometry Today(October 1998).

Example 3 Treatment of Atherosclerotic Disease

Atheromatous diseases develop as a result of lipid-laden plaques thatslowly form preferentially within the intimal walls of coronary,carotid, aortic, pelvic, femoral, popliteal and other arteriesthroughout the body, often in the presence of disturbed lipidmetabolism. Three protocols for treating these diseases according to themethods of the present invention follow:

First, as providing secondary prevention for the precipitation of acutevascular or thrombotic events (as in procoagulant cardiac patientsconsidered “at risk” and/or those patients receiving dialysis treatmentsthat predispose them to increased risks of thrombotic events andaccelerated atherogenesis), long-term weekly or bi-weekly treatmentsaccording to the present invention are contemplated, depending uponindividual patient responsiveness to treatments. Measurement of specificRAMs and the kinetics associated with their depletion within thesepatients will afford tight control of the procoagulant state. Thelong-term depletion is to be correlated with clinical symptoms as wellas disease specific testing (angiograms, stress testing,plethesmography, tissue oxygenation, PET scans, etc.). This is similarto the dose adjustments provided in the long-term management of diabeticpatients using insulin, however, such means have never been applied asin the present invention to community dwelling patients in out-patientapheresis settings who are afflicted with chronic, age-related,degenerative, atherogenic, thrombotic and/or inflammatory diseasesassociated with the accumulation and/or deposition of biologicalsubstances that result in or are associated with disturbances of bloodrheology and intrinsic endothelial cell function.

Second, in the setting of a planned vascular manipulation orintervention (bypass surgery, PTCA, etc.), reducing the incidence of anacute event or subsequent reperfusion injury can occur by a “blood prep”treatment 12 to 48 hours before the planed intervention, followed by onetreatment 24 to 48 hours post intervention and another 2 to 7 daysfollowing that. This will provide the maximal intravascular depletion ofprocoagulant substrate macromolecules integral to the occurrence of postoperative vascular complications (restenosis and thrombosis).

Third, in the setting of an acute vascular event (thrombosis), largevessel occlusion dynamics will be partially improved by the method ofBerrouschot. However, the microcirculatory insult will need both soonertreatment as well as longer-term therapy. Therefore, in accordance withthe present invention, MDF apheresis treatments should be performedimmediately upon the establishment of a thrombotic vascular complicationwithout delay, certainly less than six hours and more preferably lessthan one hour post event. Also, in addition to the method ofBerrouschot, the addition of at least 1 to 3 more treatments asdescribed herein over the next 10 days must be implemented for theslow-phase recovery of vascular and other injured tissues. Preferably,the time interval between successive Rheopheresis® blood filtrationtreatments ranges from about one day to about ten days and the totalplasma volume processed in any one week period is at least about 200% ofa patient's total plasma volume.

Example 4 Treatment of Rheumatoid Arthritis

Rheumatoid arthritis results from the destructive inflammatory reactionsoccurring in a synovial pannus associated with elevated serum levels ofRheumatoid Factor, various inflammatory proteins, immunologic globulins,integrins, and other compounds that are also found to invade thesynovial lining of the various joints involved. Elevations of thesesubstances are concomitantly found in the blood of patients with thedisease and are putatively causative. The protocol for treating thisdisease according to the methods of the present invention would besimilar, if not substantially identical to that of AMD with acuteexacerbations managed with an accelerated protocol of the type used inacute ischemic events described above.

Example 5 Treatment of Diabetes Mellitus

Diabetes mellitus is classically described as an autoimmune diseasedemonstrating profound pathological effects on the microcirculation andperipheral nervous system, with classically observed disruptions ofblood rheology associated with aldose deposition, and other disruptionsof carbohydrate metabolism measured in both the serum and tissues. Whilethe present invention may be used chronically (weekly or biweekly) tominimize the progressive damage induced by diabetes, the most likelyapplication will be in the use of the present invention as a treatmentof acute complications of the disease. According to the methods of thepresent invention described above this would involve the use ofprotocols similar, if not substantially identical, to acute vascularischemic events.

Example 6 Treatment of Alzheimer's Disease

Alzheimer's disease is associated with the formation of “neurofibrilarytangles” or accumulations of complex deposits comprised primarily of Tauproteins and beta-amyloid proteins in specific brain tissues, and mayalso be associated with decreased local blood flow to those same braintissues. A protocol for treating this disease according to the methodsof the present invention would be substantially similar to one or moreof the protocols described above.

Example 7 Treatment of Shunt Fistula Occlusions

Renal dialysis patients and other utilize vascular indwellingintravascular catheters, shunts and fistulas to provide vascular accessfor numerous serial extracorporeal procedures. Almost universally, thesepatients experience life-threatening clotting and occlusions of theseaccess modalities. A protocol for treating this type of adversethrombogenic event according to the methods of the present inventionwould be substantially similar to one or more of the protocols describedabove.

Although the present invention has been described in detail withreference to examples above, it is understood that Various modificationscan be made without departing from the spirit of the invention.Accordingly, the invention is limited only by the claims. All citedpatents and publications referred to in this application are hereinincorporated by reference in their entirety.

1-31. (canceled)
 32. A treatment protocol generator for use in a systemthat endeavors to generate disease specific treatment protocols based ona patient profile, said treatment protocol generator comprising: (a) atreatment protocol derivation means for analyzing disease specifichistorical composite patient profiles to derive treatment protocolshaving enhanced therapeutic effects; (b) an identifying means foridentifying particular data of a patient profile which will serve tooptimize the disease specific apheresis treatment; and (c) a treatmentprotocol generating means for generating treatment protocol that, whenexecuted, will enable optimization of the therapeutic effect ofapheresis treatment.
 33. The treatment protocol generator of claim 32,further comprising: (a) a comparing means for comparing said data ofsaid patient profile against a prescribed set of data to identify any ofsaid treatment protocols substantially conforming to desired therapeuticresult; and (b) classifying means for classifying said identifiedsuitable treatment protocols in order of suitability based on saidpatient profile.
 34. The treatment protocol generator of claim 32,wherein said identifying means comprises means for identifying, inaccordance with said composite historical patient profiles, data fromsaid database that will result a treatment protocol predicted to have asuperior therapeutic effect; and wherein said data includes at least oneof medical history data, physical characteristic data, medical conditiondata, diagnosis data, historical procedure data, clinical effect data,disease specific history data, physical examination data, and interviewdata.
 35. The treatment protocol generator of claim 32, wherein saidtreatment protocol generator further comprises optimal set selectingmeans for selecting an optimal set of treatment parameters based on atleast one of the following factors: (i) their respective predictedabilities to exhibit therapeutic results more closely matching saidprescribed set of therapeutic results as indicated by said compositehistorical patient profiles; (ii) their respective predicted abilitiesto validate said composite historical patient profiles; (iii) theirrespective predicted abilities to discriminate between said compositehistorical patient profiles; (iv) their respective predicted abilitiesto induce superior therapeutic response; and (v) similarity betweentheir disease specific characteristics and those in composite historicalpatient profile database whose therapeutic response most closely conformto the desired therapeutic response. 36-37. (canceled)
 38. An apheresistreatment data collection and treatment system, comprising: (a) aplurality of interconnected computer systems located at a respectiveplurality of apheresis treatment sites, said plurality of interconnectedcomputer systems being configured to receive input reflective ofapheresis treatment parameters and clinical effects produced byapheresis treatments, wherein at least one of said plurality ofinterconnected computer systems is located at a dedicated out-patientapheresis treatment facility; and (b) a centralized database systemincluding a storage facility that stores apheresis treatment parameterdata and clinical effects data that are received from said plurality ofinterconnected computer systems, said centralized database systemfurther including a means for creating a composite patient profile basedupon apheresis treatment data that is collected for patients treated atsaid plurality of apheresis treatment sites.
 39. The system of claim 38,wherein said plurality of interconnected computer systems and saidcentralized database system are interconnected to form a computernetwork.
 40. The system of claim 39, wherein said computer network isconnected to the Internet.
 41. The system of claim 40, wherein saidcomputer network utilizes a computerized data management system forcoordinating, managing, directing, entering, accessing, and analyzingall aspect of medical subspecialty-directed, disease-specific apheresisservices throughout said computer network, said data management systemcomprising: (a) at least one processing unit for processing data in saiddata management system; (b) at least one storage device for storinginformation in said data management system; and (c) a software componentfor managing and controlling said processing unit and said storagedevice.
 42. The system of claim 41, wherein said data management systemfurther comprises: (a) means for tracking apheresis patients; (b) meansfor providing real-time paperless data entry of apheresis treatmentparameters during apheresis procedures at said plurality of apheresistreatment facilities; (c) means for providing central access forreal-time remote monitoring, via a secure Internet link, of all steps insaid apheresis treatment process at said plurality of apheresistreatment facilities; and (d) means for allowing all authorized membersof said computer network to enter patient data and retrieve reports andanalysis based on all prior patients treated. 43-47. (canceled)
 48. Amethod for storing and processing input reflective of apheresistreatment parameters and clinical effects produced by apheresistreatments in a apheresis treatment data collection and treatmentsystem, said method comprising the steps of: (a) configuring a pluralityof interconnected computer systems located at a respective plurality ofapheresis treatment sites to receive input reflective of apheresistreatment parameters and clinical effects produced by apheresistreatments, wherein at least one of said plurality of interconnectedcomputer systems is located at a dedicated out-patient apheresistreatment facility; and (b) storing apheresis treatment parameter dataand clinical effects data that are received from said plurality ofinterconnected computer systems in a centralized database system, saidcentralized database system further including a means for creating acomposite patient profile based upon apheresis treatment data that iscollected for patients treated at said plurality of apheresis treatmentsites.
 49. The method of claim 48, further comprising the step ofinterconnecting said plurality of interconnected computer systems andsaid centralized database system to form a computer network.
 50. Themethod of claim 49, further comprising the step of connecting saidcomputer network is to the Internet.
 51. The method of claim 50, furthercomprising the step of utilizing, by said computer network, acomputerized data management system for coordinating, managing,directing, entering, accessing, and analyzing all-aspect of medicalsubspecialty-directed, disease-specific apheresis services throughoutsaid computer network, the method further comprises the steps of: (a)processing data in at least one processing unit in said data managementsystem; (b) storing information in at least one storage device in saiddata management system; and (c) managing and controlling said processingunit and said storage device by a software component in said datamanagement system.
 52. The method of claim 51, wherein the step ofmanaging and controlling further comprises the steps of: (a) trackingapheresis patients; (b) providing real-time paperless data entry ofapheresis treatment parameters during apheresis procedures at saidplurality of apheresis treatment facilities; (c) providing centralaccess for real-time remote monitoring, via a secure Internet link, ofall steps in said apheresis treatment process at said plurality ofapheresis treatment facilities; and (d) allowing all authorized membersof said computer network to enter patient data and retrieve reports andanalysis based on all prior patients treated. 53-54. (canceled)
 55. Themethod of claim 51, further comprising the step of expanding a softwareunit in each of said plurality of interconnected computer systems toinclude, among other information, information about additional diseases.56. The method of claim 51, further comprising the steps of: (a)initializing and indexing, by said software component, patient data,upon receiving said patient data through said apheresis treatment datacollection and treatment system; and (b) saving, by said softwarecomponent, said patient data in at least one of said storage devices inthe form of composite patient profiles.
 57. The method of claim 56,further comprising the step of using, by said software component, saidprocessing unit to: (a) process and analyze data in said patientprofiles for all patients previously treated by said medicalsubspecialty-directed, disease-specific apheresis providers within saidplurality of apheresis treatment facilities; and (b) create patientprofiles for patients currently undergoing treatment, and save createdprofiles in at least one of said storage devices.
 58. A system forstoring and processing input reflective of apheresis treatmentparameters and clinical effects produced by apheresis treatments in aapheresis treatment data collection and treatment system, said systemcomprising: (a) means for configuring a plurality of interconnectedcomputer systems located at a respective plurality of apheresistreatment sites to receive input reflective of apheresis treatmentparameters and clinical effects produced by apheresis treatments,wherein at least one of said plurality of interconnected computersystems is located at a dedicated out-patient apheresis treatmentfacility; and (b) means for storing apheresis treatment parameter dataand clinical effects data that are received from said plurality ofinterconnected computer systems in a centralized database system, saidcentralized database system further including a means for creating acomposite patient profile based upon apheresis treatment data that iscollected for patients treated at said plurality of apheresis treatmentsites.
 59. The system of claim 58, further comprising means forinterconnecting said plurality of interconnected computer systems andsaid centralized database system to form a computer network.
 60. Thesystem of claim 59, further comprising means for connecting saidcomputer network is to the Internet.
 61. The system of claim 60, furthercomprising means for utilizing, by said computer network, a computerizeddata management system for coordinating, managing, directing, entering,accessing, and analyzing all aspect of medical subspecialty-directed,disease-specific apheresis services throughout said computer network,the system further comprises: (a) means for processing data in at leastone processing unit in said data management system; (b) means forstoring information in at least one storage device in said datamanagement system; and (c) means for managing and controlling saidprocessing unit and said storage device by a software component in saiddata management system.
 62. The system of claim 61, wherein said meansfor managing and controlling further comprises: (a) means for trackingapheresis patients; (b) means for providing real-time paperless dataentry of apheresis treatment parameters during apheresis procedures atsaid plurality of apheresis treatment facilities; (c) means forproviding central access for real-time remote monitoring, via a secureInternet link, of all steps in said apheresis treatment process in saidplurality of apheresis treatment facilities; and (d) means for allowingall authorized members of said computer network to enter patient dataand retrieve reports and analysis based on all prior patients treated.63-67. (canceled)
 68. An apheresis treatment data collection andtreatment system, comprising: (a) first means for enabling a user toenter information about a patient in a computer database; (b) secondmeans for creating a summary of the information entered into the localcomputer database; (c) third means for periodically transmitting thesummarized information to a data management system database; (d) fourthmeans for allowing local users to search the data management systemdatabase for a specific patient profile; (e) fifth means for performingdata aggregation and analysis on the data management system database andfor producing reports based on a search criterion; and (f) sixth meansfor allowing the local users to download the produced reports.
 69. Thesystem of claim 68, wherein the sixth means for allowing enableslicensed users to establish the efficacy of RheoTherapy®.
 70. The systemof claim 69, wherein the first means for allowing enables licensed usersto input data for each patient on several transaction forms, thetransaction forms are accessed from a main switchboard in the dataprocessing system. 71-77. (canceled)